ArticleLiterature Review

Mechanisms of Disease: Oncogene addiction - A rationale for molecular targeting in cancer therapy

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Abstract

There has been considerable progress in the systemic treatment of cancer because of the rapid development and clinical application of molecular targeted agents. Although patients with a particular type and stage of cancer are often treated as a single group, more-specific therapy is being considered, as subsets of these patients who are more likely to benefit from treatment with particular agents are being identified. We previously introduced the concept of 'oncogene addiction' to explain how some cancers that contain multiple genetic, epigenetic, and chromosomal abnormalities are dependent on or 'addicted' to one or a few genes for both maintenance of the malignant phenotype and cell survival. Thus, reversal of only one or a few of these abnormalities can inhibit cancer cell growth and in some cases translate to improved survival rates. This review summarizes current experimental and clinical evidence for the concept of oncogene addiction and describes molecular mechanisms that may explain this phenomenon. In addition, we discuss how high-throughput screening methods, including gene-expression profiling and proteomics, and emerging methods for analyzing complex cellular networks can be used to identify the state of oncogene addiction, i.e. the 'Achilles' heel,' in specific cancers. Finally, we discuss the use of molecular targeted agents in combination with other anticancer agents as a strategy to optimize therapy and prevent disease recurrence.

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... 1) Rethinking oncogene addiction. 4 Oncogene addiction refers to the reliance of cancer cells on one or more genes for their survival (38,39). As a result, inhibiting the proteins corresponding to these oncogenes can lead to a complete halt or regression in tumor growth (38,39). ...
... 4 Oncogene addiction refers to the reliance of cancer cells on one or more genes for their survival (38,39). As a result, inhibiting the proteins corresponding to these oncogenes can lead to a complete halt or regression in tumor growth (38,39). This concept of ʺaddictionʺ explains the selectivity and effectiveness seen in certain molecularly targeted therapies currently used in clinical practice despite the common occurrence of resistance at later stages of treatment (38,39,40,41,42). ...
... As a result, inhibiting the proteins corresponding to these oncogenes can lead to a complete halt or regression in tumor growth (38,39). This concept of ʺaddictionʺ explains the selectivity and effectiveness seen in certain molecularly targeted therapies currently used in clinical practice despite the common occurrence of resistance at later stages of treatment (38,39,40,41,42). ...
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Tumor heterogeneity is a major obstacle to achieving consistent outcomes in cancer therapy. We offer a novel perspective on tumor heterogeneity, informed by an advanced understanding of tumor evolution. We understand any cells, or any organism, will inherently respond with specific capacities when faced with adversity. Our concepts, which extend beyond canonical views, posit that tumor evolution is driven by cellular responses to survival challenges. The disease is driven by a rudimentary action taken by any organism when confronted with adversity - a cellular response to generate specific capacities to overcome the threat - the responses that utilize advantageous genetic mutations and other cellular contents to attain these capacities and further drive the disease. The disease is initiated by a cellular response to survival challenges and the ongoing development of hallmark cancer capabilities, as cells endeavor to obtain a competitive advantage, results in increased molecular disarray, observed as tumor heterogeneity. When the evolutionary drive for survival is impeded by therapeutic inhibition of critical genes, cell death occurs, a phenomenon termed oncogene addiction. Drawing from the same idea that cells responding to survival challenges, we recognize the increasing primitiveness of cancer during its progress stems from the innate cellular response to the demand for regeneration under sustained cellular damage. This necessitates a regression to a more primitive state purposed to renew progeny, unleashing a hitherto undiscerned cellular capacity. Taken together, the ideas explored herein pave the way for novel cancer therapies and the betterment of human health.
... Oncogene addiction refers to the reliance of cancer cells on one or more genes for their survival (38,39). As a result, inhibiting the proteins corresponding to these oncogenes can lead to a complete halt or regression in tumor growth (38,39). ...
... Oncogene addiction refers to the reliance of cancer cells on one or more genes for their survival (38,39). As a result, inhibiting the proteins corresponding to these oncogenes can lead to a complete halt or regression in tumor growth (38,39). This concept of "addiction" explains the selectivity and effectiveness seen in certain molecularly targeted therapies currently used in clinical practice despite the common occurrence of resistance at later stages of treatment (38,39,40,41,42). ...
... As a result, inhibiting the proteins corresponding to these oncogenes can lead to a complete halt or regression in tumor growth (38,39). This concept of "addiction" explains the selectivity and effectiveness seen in certain molecularly targeted therapies currently used in clinical practice despite the common occurrence of resistance at later stages of treatment (38,39,40,41,42). ...
Preprint
Full-text available
Tumor heterogeneity is a major obstacle to achieving consistent outcomes in cancer therapy. Here, we present a new perspective on tumor heterogeneity. The foundation for understanding tumor heterogeneity lies in recognizing that tumor evolution is a process driven by cells responding to survival challenges, and this cellular response precipitates the development of hallmark cancer capabilities. We posit that tumor heterogeneity arises from cells’ continued development of hallmark cancer capabilities, which ultimately leads to increased molecular chaos. Therapeutic inhibition of the essential genes driving the disease can disrupt tumor evolution, leading to cell death, a phenomenon termed oncogene addiction. Drawing from the same idea that cells respond to survival challenges, we introduce the notion that the increasing primitiveness of cancer during its progress stems from the cellular response to the continuous need for regeneration due to sustained cellular damage. To expand our concept of tumor heterogeneity, we further explore redefining key genes based on heterogeneity levels, and we propose a potential treatment strategy for advanced-stage cancers based on inducing aging-related deterioration. Taken together, the notions explored herein pave the way for novel cancer therapies and the betterment of human health.
... Thus PK inhibitors are a promising tool in curbing the PKs dysregulation in such disorders [9][10][11][12] . In oncotherapy, protein kinases inhibitors constitute a main continuously growing category of targeted chemotherapies that is free of the traditional cancer chemotherapy common side actions as they target the signalling pathways and microenvironment of the cancer cells with minor adverse actions on normal mammalian cells [13][14][15][16] . ...
... The structure of intermediates 6, 7 as well as those of target compounds 9, 11, 13, 15 and 17 were confirmed by 1 H as well as 13 C NMR spectral analysis (see the NMR charts in the supplementary material). All of the relevant spectral data of these compounds shared some common NMR signals. ...
Article
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In the current work, a hybridisation strategy was adopted between the privileged building blocks, benzofuran and piperazine, with the aim of designing novel CDK2 type II inhibitors. The hybrid structures were linked to different aromatic semicarbazide, thiosemicarbazide, or acylhydrazone tails to anchor the designed inhibitors onto the CDK2 kinase domain. The designed compounds showed promising CDK2 inhibitory activity. Compounds 9h, 11d, 11e and 13c showed potent inhibitory activity (IC50 of 40.91, 41.70, 46.88, and 52.63 nM, respectively) compared to staurosporine (IC50 of 56.76 nM). Moreover, benzofurans 9e, 9h, 11d, and 13b showed promising antiproliferative activities towards different cancer cell lines, and non-significant cytotoxicity on normal lung fibroblasts MRC-5 cell line. Furthermore, a cell cycle analysis as well as Annexin V-FITC apoptosis assay on Panc-1 cell line were performed. Molecular docking simulations were performed to explore the ability of target benzofurans to adopt the common binding pattern of CDK2 type II inhibitors.
... In the search for therapeutic targets, special attention is required to identify single or multiple genes required for both the malignant phenotype and the survival of cancer cells. These are generally considered as oncogene addictions [58]. In lung cancer, commonly activated oncogenes may include MYC, KRAS, MET, CCND1, EGFR/HER1/ERBB1, HER2/ERBB2, EML4-ALK fusion, CDK4, and BCL-2 [59]. ...
Chapter
Book series on Medical Science gives the opportunity to students and doctors from all over the world to publish their research work in a set of Preclinical sciences, Internal medicine, Surgery and Public Health. This book series aim to inspire innovation and promote academic quality through outstanding publications of scientists and doctors. It also provides a premier interdisciplinary platform for researchers, practitioners, and educators to publish the most recent innovations, trends, and concerns as well as practical challenges encountered and solutions adopted in the fields of Medical Science. It also provides a remarkable opportunity for the academic, research and doctors communities to address new challenges and share solutions.
... As a result of the increased expression of basal Bid/tBid protein following accumulated DNA damage [42], certain tumor cells exhibit a peculiar dependence on this pro-apoptotic factor [63][64][65][66][67]. Describing these cells as "addicted" to Bid underscores their reliance on its presence for maintaining viability and highlights a unique vulnerability that can be exploited therapeutically. Indeed, such cells become markedly more susceptible to treatments aimed at modulating the cellular abundance or functionality of Bid. ...
Article
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Effective cancer therapy with limited adverse effects is a major challenge in the medical field. This is especially complicated by the development of acquired chemoresistance. Understanding the mechanisms that underlie these processes remains a major effort in cancer research. In this review, we focus on the dual role that Bid protein plays in apoptotic cell death via the mitochondrial pathway, in oncogenesis and in cancer therapeutics. The BH3 domain in Bid and the anti-apoptotic mitochondrial proteins (Bcl-2, Bcl-XL, mitochondrial ATR) it associates with at the outer mitochondrial membrane provides us with a viable target in cancer therapy. We will discuss the roles of Bid, mitochondrial ATR, and other anti-apoptotic proteins in intrinsic apoptosis, exploring how their interaction sustains cellular viability despite the initiation of upstream death signals. The unexpected upregulation of this Bid protein in cancer cells can also be instrumental in explaining the mechanisms behind acquired chemoresistance. The stable protein associations at the mitochondria between tBid and anti-apoptotic mitochondrial ATR play a crucial role in maintaining the viability of cancer cells, suggesting a novel mechanism to induce cancer cell apoptosis by freeing tBid from the ATR associations at mitochondria.
... 9 Cancer cells often depend on a single oncogenic pathway for survival, a concept known as oncogene addiction. 11 Oncogenic drivers are usually mutually exclusive due to one actionable gene lesion in the cancer genome. 12,13 Conversely, 1% to 3% of patients may harbor co-occurring gene alterations. ...
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Background Since the publication of the original work in 2014, significant progress has been made in the characterization of genomic alterations that drive oncogenic addiction of nonsmall cell lung cancer (NSCLC) and how the immune system can leverage non-oncogenic pathways to modulate therapeutic outcomes. This update evaluates and validates the recent and emerging data for prognostic and predictive biomarkers with therapeutic targets in NSCLC. Data sources We performed a literature search from January 2015 to October 2023 using the keywords non-small cell lung cancer, clinical practice guidelines, gene mutations, genomic assay, immune cancer therapy, circulating tumor DNA, predictive and prognostic biomarkers, and targeted therapies. Study selection and data extraction We identified, reviewed, and evaluated relevant clinical trials, meta-analyses, seminal articles, and published clinical practice guidelines in the English language. Data synthesis Regulatory-approved targeted therapies include those somatic gene alterations of EGFR (“classic” mutations, exon 20 insertion, and rare EGFR mutations), ALK, ROS1, BRAF V600, RET, MET, NTRK, HER2, and KRAS G12C. Data for immunotherapy and circulating tumor DNA in next-generation sequencing are considered emerging, whereas the predictive role for PIK3CA gene mutation is insufficient. Conclusions Advances in sequencing and other genomic technologies have led to identifying novel oncogenic drivers, novel resistance mechanisms, and co-occurring mutations that characterize NSCLC, creating further therapeutic opportunities. The benefits associated with immunotherapy in the perioperative setting hold initial promise, with their long-term results awaiting.
... Moreover, about 20-25% of individuals with airway hyperresponsiveness, ingesting SO 2 at levels ranging from 0.25 to 2 mg/ L may lead to bronchoconstriction (Vally, Misso, & Madan, 2006). Furthermore, SO 2 has been shown to activate the proto-oncogenes, causing normal cells to become cancerous when mutated (Weinstein & Joe, 2006), and inactivate tumour suppresser genes (Qin & Meng, 2009;Santos et al., 2012). The World Health Organisation (WHO) has recommended limiting SO 2 as much as possible or even completely removing SO 2 from the treatment of foods (World Health Organization, 2009). ...
Article
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This study examines the feasibility of replacing SO2 in a New Zealand Sauvignon Blanc wine with a green tea extract. The treatments included the control with no preservatives (C), the addition of green tea extract at 0.1 and 0.2 g/L (T1 and T2), and an SO2 treatment at 50 mg/L (T3). Five monomeric phenolic compounds were detected in the green tea extract used for the experiment, and their concentrations ranged in the order (−)-epigallocatechin gallate > (−)-epigallocatechin > (−)-epicatechin > (−)-epicatechin gallate > gallic acid. At the studied addition rates, these green tea-derived phenolic compounds contributed to ~70% of the antioxidant capacity (ABTS), ~71% of the total phenolic index (TPI), and ~ 84% of tannin concentration (MCPT) of the extract dissolved in a model wine solution. Among wine treatments, T1 and T2 significantly increased the wine's colour absorbance at 420 nm, MCPT, gallic acid and total monomeric phenolic content. TPI and ABTS were significantly higher in wines with preservatives (i.e., T2 > T1 ≅ T3 > C, p < 0.05). These variations were observed both two weeks after the treatments and again after five months of wine aging. Additionally, an accelerated browning test and a quantitative sensory analysis of wine colour and mouthfeel attributes were performed after 5 months of wine aging. When exposed to excessive oxygen and high temperature (50 °C), T1 and T2 exhibited ~29% and 24% higher browning capacity than the control, whereas T3 reduced the wine's browning capacity by ~20%. Nonetheless, the results from sensory analysis did not show significant variations between the treatments. Thus, using green tea extract to replace at wine bottling appears to be a viable option, without inducing a negative impact on the perceptible colour and mouthfeel attributes of Sauvignon Blanc wine.
... The binding site was obtained using the BIOVIA Discovery Studio software [44]. The results of the visualization were the ligand interactions with amino acids in protein macromolecules. ...
Conference Paper
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Liver cancer is currently a leading cause of death worldwide and its incidence is increasing. As a result, there has been an increase in the development of computational drug design strategies utilizing molecules for anti-cancer candidates over the last decade. DNA topoisomerase II (topo II) enzymes play a crucial role in regulating essential cellular processes by altering the topology of chromosomal DNA. The PDGF receptor is a promising anti-cancer target and is used as a prognostic marker for liver cancer due to its ability to interact with topo II enzymes. Trisindoline 5’-nitro-[3,3 ’: 3’, 3”-terindoline]-2’-one is a cytotoxic indole trimer alkaloid compound that induces apoptosis in the HepG2 cell line. This study investigated the potential of Trisindoline 1 as an alternative drug for liver cancer by conducting molecular docking against topo II and PDGF. The binding energy value of Trisindoline 1 against human topo II was -10.1 Kcal/mol, which was higher than the binding energy value of doxorubicin (-9.2 Kcal/mol). Furthermore, pharmacophore analysis of Trisindoline 1 indicated that it possesses drug-like properties and lower toxicity than doxorubicin. Trisindoline 1 has the potential to inhibit PDGF and human topo II enzymes in liver cancer through the apoptotic pathway.
... The former category includes the TNBC cell line DU-4475 and the CRC cell line Colo-205, which are killed via apoptosis due to BRAF degradation or inhibition by either SJF-0628 or dabrafenib. Thus, these cells appear to be "addicted" to a single oncogenic driver, BRAF V600E, according to the oncogene addiction hypothesis [54,55]. Cancers utilizing such a mono-driver mechanism are likely responsive to targeted therapy in a clinical setting. ...
Article
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Simple Summary The BRAF V600E mutation is frequently found in cancer. It activates the MAPK pathway and promotes cancer cell proliferation, making BRAF an excellent target for anti-cancer therapy. While BRAF-targeted therapy is highly effective for melanoma, it is often ineffective against other cancers. This study uses a proteolysis targeting chimera (PROTAC) to probe the role of BRAF V600E in colorectal and triple-negative breast cancer cells. The study reveals a diverse set of biochemical and proliferative responses to BRAF V600E degradation: some cancer cells are killed by BRAF degradation, while others utilize additional oncogenic drivers, such as Src kinase phosphatidylinositol 3-kinase, to resist the effect of BRAF degradation. These responses provide a mechanistic explanation for the efficacy of BRAF-targeted therapy for some cancers and the intrinsic resistance in others. Abstract The BRAF V600E mutation is frequently found in cancer. It activates the MAPK pathway and promotes cancer cell proliferation, making BRAF an excellent target for anti-cancer therapy. While BRAF-targeted therapy is highly effective for melanoma, it is often ineffective against other cancers harboring the BRAF mutation. In this study, we evaluate the effectiveness of a proteolysis targeting chimera (PROTAC), SJF-0628, in directing the degradation of mutated BRAF across a diverse panel of cancer cells and determine how these cells respond to the degradation. SJF-0628 treatment results in the degradation of BRAF V600E and a decrease in Mek activation in all cell lines tested, but the effects of the treatment on cell signaling and cell proliferation are cell-line-specific. First, BRAF degradation killed DU-4475 and Colo-205 cells via apoptosis but only partially inhibited the proliferation of other cancer cell lines. Second, SJF-0628 treatment resulted in co-degradation of MEK in Colo-205 cells but did not have the same effect in other cell lines. Finally, cell lines partially inhibited by BRAF degradation also contain other oncogenic drivers, making them multi-driver cancer cells. These results demonstrate the utility of a PROTAC to direct BRAF degradation and reveal that multi-driver oncogenesis renders some colorectal cancer cells resistant to BRAF-targeted treatment.
... Entrectinib is a central nervous systems (CNS)active, shown to have antitumor activity in advanced and metastatic solid tumors by inhibiting tyrosine receptor kinases (TRK) A, B, and C, tyrosine kinase ROS proto-oncogene 1 (reactive oxygen species; ROS1), and anaplastic lymphoma kinase (ALK) [1,2]. Entrectinib received its first global approval in Japan for the treatment of advanced or recurrent solid tumors, whereas the U. S. Food and Drug Administration approved for the treatment of adults with lung cancer and granted accelerated approval for the treatment of adult and pediatric patients with neurotrophic TRK fusion-positive solid tumors [3]. ...
Article
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Objective: As Entrectinib is a lipophilic, basic, moderately permeable molecule with strongly pH-dependent solubility with antitumor activity in advanced and metastatic solid tumors, the current study was designed to improve the oral solubility of Entrectinib through incorporation into nanosponges tablets (NSs). Methods: Box-Behnken Design was used to optimize the independent variables of β-Cyclodextrin (β-CD) NSs formation. β-CD NSs were prepared by an ultrasound-assisted method using diphenyl carbonate as cross-linking agent, which were later characterized and formulated into tablets by wet granulation method. The prepared tablets were evaluated for the physico-chemical properties and in vitro release of the drug. Results: A series of fifteen experiments were performed based on the experimental runs generated from a three-factor, three-level Box–Behnken design (BBD). The range of mean particle size was 149-294 nm, the range for encapsulation efficiency % was 65.4%-87.3%, and the value for polydispersity index was 0.437. The zeta potential for the optimized formulation was found to be 38.1 Mv. The drug and excipients were compatibles as confirmed by Fourier Transformed Infrared (FTIR) Spectroscopy and Differential Scanning Calorimetry (DSC) studies. Scanning Electron Microscopic (SEM) analysis confirmed that the Entrectinib has successfully entrapped in the core of polymer. In vitro release of the Entrectinib-loaded NSs tablets (six compositions) were compared with a marked product and satisfactory results were obtained. It was observed that rapid dissolution occurred in 0.1 N HCl for first 2 h (15.64±1.52% vs. 12.67±1.89%) and 98.94±2.43% of drug release was observed in Entrectinib loaded NSs and 91.78±1.37% in marketed product in 24 h. The prepared formulations were stable during 6 mo stability study period. Conclusion: The study results studies of Entrectinib NS tablets indicated rapid dissolution due to changed solubility properties of the drug, compared to pure drug meeting the set objective of enhanced absorption. The formulated Entrectinib-loaded NSs can be beneficial in the treatment of cancers.
... Overall, chronic and cumulative exposure to UVR is the single most significant etiological environmental issue-induced skin carcinogenesis for both non-melanoma skin cancer and melanoma, the oncogenic pathway, mutation ranges and tumor suppression genes are relatively cell-specific. 25 UVB is directly absorbed by DNA and thus causes DNA injury and changes in gene expression by intracellular signaling transduction, which leads to skin cancer. UVA irradiation can yield reactive oxygen free radicals, which cause secondary harm to DNA, and thus develop skin cancer. ...
... Importantly, the presence of EGFR mutations predicts response to specific tyrosine kinase inhibitors (TKIs), likely due to addiction of the respective tumor cells to an active EGFR pathway [6]. The most frequent gene aberration of HER2/ERBB2, the closest homologue of EGFR, is gene amplification, which occurs in breast, gastric and other tumors, but rare missense mutations have also been reported [7,8]. ...
Article
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Simple Summary Genome-based cancer medicine is becoming the standard of care: the patient’s tumor DNA is first analyzed to identify driver mutations, and this permits later selection of the most effective drugs. Treatment of lung cancer offers many examples. Activating mutations in the epidermal growth factor receptor (EGFR) gene, as well as in other receptor tyrosine kinases (e.g., ALK), are considered actionable candidates, and the respective drugs, called tyrosine kinase inhibitors, are relatively effective. Unfortunately, despite initial activity, the emergence of new, on-target mutations, along with adaptive processes, preempt the anti-cancer effects and necessitate switching to next-generation drugs. This review highlights recent progress in resolving the mechanisms that underlie acquisition of resistance. Specifically, we focus on the endogenous mutators that initiate emergence of new mutations and the potential clinical benefits that may be derived from this new understanding. Abstract Epidermal growth factor receptor (EGFR)-specific tyrosine kinase inhibitors (TKIs) have changed the landscape of lung cancer therapy. For patients who are treated with the new TKIs, the current median survival exceeds 3 years, substantially better than the average 20 month survival rate only a decade ago. Unfortunately, despite initial efficacy, nearly all treated patients evolve drug resistance due to the emergence of either new mutations or rewired signaling pathways that engage other receptor tyrosine kinases (RTKs), such as MET, HER3 and AXL. Apparently, the emergence of mutations is preceded by a phase of epigenetic alterations that finely regulate the cell cycle, bias a mesenchymal phenotype and activate antioxidants. Concomitantly, cells that evade TKI-induced apoptosis (i.e., drug-tolerant persister cells) activate an intrinsic mutagenic program reminiscent of the SOS system deployed when bacteria are exposed to antibiotics. This mammalian system imbalances the purine-to-pyrimidine ratio, inhibits DNA repair and boosts expression of mutation-prone DNA polymerases. Thus, the net outcome of the SOS response is a greater probability to evolve new mutations. Deeper understanding of the persister-to-resister transformation, along with the development of next-generation TKIs, EGFR-specific proteolysis targeting chimeras (PROTACs), as well as bispecific antibodies, will permit delaying the onset of relapses and prolonging survival of patients with EGFR⁺ lung cancer.
... Targeted therapy often takes advantage of molecular targets involved in the aberrant physiology of cancer cells relative to normal cells [9][10][11]. Overexpressed, amplified or oncogenic mutations of proto-oncogenes are a favorable target for this purpose [10,12,13]. Another strategy is taking advantage of synthetic lethality, where inhibition of one gene is not enough to result in cell death, but an additional gene simultaneously does [14][15][16][17]. ...
Article
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Ubiquitination is a post-translational modification (PTM) that is involved in proteolysis, protein–protein interaction, and signal transduction. Accumulation of mutations and genomic instability are characteristic of cancer cells, and dysfunction of the ubiquitin pathway can contribute to abnormal cell physiology. Because mutations can be critical for cells, DNA damage repair, cell cycle regulation, and apoptosis are pathways that are in close communication to maintain genomic integrity. Uncontrolled cell proliferation due to abnormal processes is a hallmark of cancer, and mutations, changes in expression levels, and other alterations of ubiquitination factors are often involved. Here, three E3 ubiquitin ligases will be reviewed in detail. RNF126, RNF168 and CUL1 are involved in DNA damage response (DDR), DNA double-strand break (DSB) repair, cell cycle regulation, and ultimately, cancer cell proliferation control. Their involvement in multiple cellular pathways makes them an attractive candidate for cancer-targeting therapy. Functional studies of these E3 ligases have increased over the years, and their significance in cancer is well reported. There are continuous efforts to develop drugs targeting the ubiquitin pathway for anticancer therapy, which opens up the possibility for these E3 ligases to be evaluated for their potential as a target protein for anticancer therapy.
... Oncoproteins are appealing therapeutic targets due to their involvement in malignant cell behavior (116). Given its importance in PTC, cyclin D1 has come to be considered as an attractive drug target for clinical treatments. ...
Article
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Cyclin D1 functions as a mitogenic sensor that specifically binds to CDK4/6, thereby integrating external mitogenic inputs and cell cycle progression. Cyclin D1 interacts with transcription factors and regulates various important cellular processes, including differentiation, proliferation, apoptosis, and DNA repair. Therefore, its dysregulation contributes to carcinogenesis. Cyclin D1 is highly expressed in papillary thyroid carcinoma (PTC). However, the particular cellular mechanisms through which abnormal cyclin D1 expression causes PTC are poorly understood. Unveiling the regulatory mechanisms of cyclin D1 and its function in PTC may help determine clinically effective strategies, and open up better opportunities for further research, leading to the development of novel PTC regimens that are clinically effective. This review explores the mechanisms underlying cyclin D1 overexpression in PTC. Furthermore, we discuss the role of cyclin D1 in PTC tumorigenesis via its interactions with other regulatory elements. Finally, recent progress in the development of therapeutic options targeting cyclin D1 in PTC is examined and summarized.
... 62 Proto-oncogenes are normal genes that, when mutated, influence the growth of normal cells to be cancerous. 63,64 The mutated proto-oncogene can also be understood as an oncogene where a gene that used to be viable for normal human function becomes overexpressed, causing continuous and uncontrollable growth of cells, thereby leading to cancer. The primary function of proto-oncogenes revolves around cellular division and inhibition of cell differentiation and apoptosis. ...
Article
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Cancer is a leading cause of mortality and morbidity globally. Sex differences in cancer are evident in death rates and treatment responses in several cancers. Asian patients have unique cancer epidemiology influenced by their genetic ancestry and sociocultural factors in the region. In this review, we show molecular associations that potentially mediate sex disparities observed in cancer in the Asian population. Differences in sex characteristics are evident at the cytogenetic, genetic, and epigenetic levels mediating processes that include cell cycle, oncogenesis, and metastasis. Larger clinical and in vitro studies that explore mechanisms can confirm the associations of these molecular markers. In-depth studies of these markers can reveal their importance as diagnostics, prognostics, and therapeutic efficacy markers. Sex differences should be considered in designing novel cancer therapeutics in this era of precision medicine.
... The concept of oncogene addition defines the process by which some cancers remain highly dependent on one specific genetic aberration for cellular proliferation and survival. 2 BRAF mutations can be found in approximately 2% of NSCLCs, most commonly in lung adenocarcinomas (LUADs) and particularly in those with aggressive histologic features like the micropapillary subtype. 9 Activating V600E/V600K/V600D/V600R mutations in the tyrosine kinase domain (class I mutations) represent approximately 50% of BRAF-mutant NSCLCs. ...
Article
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Precision oncology comprises the set of strategies that aim to design the best cancer treatment based on tumor biology. A recognized subset of patients with non‐small cell lung cancer (NSCLC) harbor actionable genomic aberrations that can benefit from targeted therapy. In lung cancer, epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are well characterized oncogenic drivers for which the therapeutic use of tyrosine kinase inhibitors has demonstrated improved outcomes compared with chemotherapy. Other druggable targets are also well characterized, and effective inhibitors have been developed and commercialized, leading to a paradigm shift in NSCLC treatment. Here, the authors provide a review of the oncogenic role of the most relevant molecular alterations in NSCLC and emerging treatments in this setting beyond EGFR‐driven and ALK‐driven diseases.
... Inhibition of the tropomyosin-related kinase (TRK) proteins A, B, and C, receptor tyrosine kinase (ROS1), and anaplastic lymphoma kinase (ALK) protein leads to inhibition of downstream signaling pathways, which in turn suppresses cell proliferation and apoptosis. It is interesting to note that entrectinib is CNS active and could cross the blood-brain barrier to inhibit the tumor growth and is reported to have anticancer activity in progressive and metastatic solid tumors [1][2][3]. Entrectinib was first time approved in May 2017 by USFDA with breakthrough designation for the treatment of adult and pediatric patients with NTRK fusion-positive solid tumors [4]. The recommended dose of entrectinib was 600 mg/day for adults and 300 mg /day for children aged 12 years or older [5]. ...
Article
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Entrectinib is a novel potent anticancer drug with poor aqueous solubility. A supersaturable self-nanoemulsifying drug delivery system of entrectinib is developed using a super saturation promoter. The components of the isotropic mixture of SNEDDS were selected based on solubility and emulsification study. The optimum composition was identified using phase diagrams and further optimized by mixture design. The supersaturated SNEDDS was prepared using HPMC K4M as precipitation inhibitor. The droplet of sSNEDDS ranges from 118.42 ± 1.26 to 128.34 ± 0.63 nm with PDI values range from 0.112 to 0.204, which is significantly smaller than that observed with plain SNEDDS. The percent transmittance of the diluted formulation was found to be 98.78 ± 0.74. The viscosity was found to be 528 ± 32 centipoises indicating the good flow ability. FTIR and DSC studies indicated the amorphization of the drug. The dissolution profile of sSNEDDS indicated the faster release of drug compared to both pure drug suspension and SNEDDS formulation. The drug release rate is directly proportional to the concentration of the drug. The drug release from the insoluble matrix is a square root of time-dependent Fickian diffusion process. The formulation was found to be stable and transparent at all pH values and the percent transmittance was more than 95%. No significant difference was observed with all the samples exposed at different storage conditions. This study demonstrated the feasibility of stabilizing and improving the in vitro performance of SNEDDS by incorporating HPMC K4M as precipitation inhibitor. Graphical abstract
... Global cancer data indicate that cancer is the second most common cause of death worldwide. The prevention, identification, and treatment of cancer have made significant strides in recent years [1][2][3]. Chemotherapy, radiation therapy, and surgery are the three most popular treatment options. Several anticancer agents, often known as antineoplastic drugs, are utilized in chemotherapy. ...
Article
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Due to less sensitivity of graphene towards the cisplatin (CPT), the graphene is modified by doping systematically boron atoms (B/Gra), nitrogen atoms (N/Gra), and hexagonal boron nitride (BN/Gra) to form hetero-quantum dots (QDs). In our DFT investigations, the CPT drug adsorbs on the surface of modified QDs within favorable range of adsorption energy. Among them, B/Gra QD shows high adsorption behavior with CPT at about −1.44 eV and −0.6 eV energies in gas and water solvent phases. On the other hand, BN/Gra and N/Gra hetero-QDs interact with CPT at about −0.88 eV and −1.03 eV adsorption energies respectively. During interaction of CPT with B/Gra, CPT loses 0.215 e and 0.129 e charge to the B/Gra in gas and solvent phases. About 26.4% and 14% reductions of E g have been occurred after the interaction of CPT with B/ Gra. Furthermore quantum molecular descriptors also suggest the high sensitivity of the B/Gra QDs with the CPT. Therefore, B/Gra QD can be used as drug carrier for CPT.
... Although antiangiogenic TKIs have provided enormous survival benefits to patients with HCC [25,43], devising optimal treatment strategies using systemic chemotherapy for HCC is becoming increasingly complex. Although various antiangiogenic TKIs have been approved for HCC treatment, the general therapeutic action of antiangiogenic TKIs involves inducing the TME into severe hypoxia via its antiangiogenic effects [44]. We discovered that IGFBP-1 expression, upregulated by hypoxia in tumors, was involved in the acquisition of antiangiogenic TKI resistance, through which tumors exerted antiangiogenic TKI-independent neoangiogenic effects. ...
Article
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Background: Antiangiogenic tyrosine kinase inhibitors (TKIs) provide one of the few therapeutic options for effective treatment of hepatocellular carcinoma (HCC). However, patients with HCC often develop resistance toward antiangiogenic TKIs, and the underlying mechanisms are not understood. The aim of this study was to determine the mechanisms underlying antiangiogenic TKI resistance in HCC. Methods: We used an unbiased proteomic approach to define proteins that were responsible for the resistance to antiangiogenic TKIs in HCC patients. We evaluated the prognosis, therapeutic response, and serum insulin-like growth factor-binding protein-1 (IGFBP-1) levels of 31 lenvatinib-treated HCC patients. Based on the array of results, a retrospective clinical study and preclinical experiments using mouse and human hepatoma cells were conducted. Additionally, in vivo genetic and pharmacological gain- and loss-of-function experiments were performed. Results: In the patient cohort, IGFBP-1 was identified as the signaling molecule with the highest expression that was inversely associated with overall survival. Mechanistically, antiangiogenic TKI treatment markedly elevated tumor IGFBP-1 levels via the hypoxia-hypoxia inducible factor signaling. IGFBP-1 stimulated angiogenesis through activation of the integrin α5β1-focal adhesion kinase pathway. Consequently, loss of IGFBP-1 and integrin α5β1 by genetic and pharmacological approaches re-sensitized HCC to lenvatinib treatment. Conclusions: Together, our data shed light on mechanisms underlying acquired resistance of HCC to antiangiogenic TKIs. Antiangiogenic TKIs induced an increase of tumor IGFBP-1, which promoted angiogenesis through activating the IGFBP-1-integrin α5β1 pathway. These data bolster the application of a new therapeutic concept by combining antiangiogenic TKIs with IGFBP-1 inhibitors.
... Kanserler genel olarak çoklu genetik ve epigenetik anormallikler içermekte fakat birkaç anahtar gen sayesinde malign fenotip ve hücresel sağkalımın devamlılığı sağlanmaktadır 1,2 . Bu genler PI3K-Akt yolağı gibi önemli sinyal yollarına etkide bulunmaktadır. ...
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Kanserler genel olarak çoklu genetik ve epigenetik anormallikler içermekte fakat birkaç anahtar gen sayesinde malign fenotip ve hücresel sağkalımın devamlılığı sağlanmaktadır. PI3K/Akt/mTOR yolağı önemli birçok fizyolojik olaylarda rol alan merkezi bir sinyal akım sistemidir. PI3K/Akt/mTOR yolağı birçok tümör çeşidi tarafından kullanıldığından bu yolağa karşı kullanılan inhibitörlerin geniş bir terapötik etkinliğinin olabileceği düşünülmektedir. Tekli tedavide bu inhibitörlerin hiçbiri ile faz 1 çalışmalarda önemli cevap oranları elde edilememiş olup yüksek dozların kısa sürelerde verilmesi ve değişik yolaklara etkili olabilecek ilaçların kombine edilmesi gibi diğer seçenekler araştırılmaktadır.
... Proto-oncogenes are a set of genes that on mutation convert the normal cells to cancerous cells (Adamson 1987;Weinstein and Joe 2006), and the mutated form of the genes are called oncogenes. Proto-oncogenes usually encode for the proteins that are involved in cell division, inhibit cell differentiation, and arrest cellular death. ...
... TRK and ROS1 fusion proteins constitutively activate tyrosine kinases and continue to emit survival and proliferation signals, resulting in overgrowth and prolonged survival of tumor cells. [3][4][5] NTRK rearrangements have been identified in a variety of cancers, with positivity rates varying depending on the type of cancer. ROS1 rearrangement has been reported in 1-2% of non-small cell lung cancers (NSCLC). ...
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Background: Entrectinib is an effective drug for treating solid tumors with NTRK gene rearrangement and non-small cell lung cancer (NSCLC) with ROS1 gene rearrangement. However, its efficacy is limited by tolerance and acquired resistance, the mechanisms of which are not fully understood. The growth factors produced by the tumor microenvironment, including hepatocyte growth factor (HGF) produced by tumor-associated fibroblasts, critically affect the sensitivity to targeted drugs. Methods: We investigated whether growth factors that can be produced by the microenvironment affect sensitivity of NTRK1-rearranged colon cancer KM12SM cells and ROS1-rearranged NSCLC HCC78 cells to entrectinib both in vitro and in vivo. Results: Among the growth factors assessed, HGF most potently induced entrectinib resistance in KM12SM and HCC78 cells by activating its receptor MET. HGF-induced entrectinib resistance was reversed by the active-HGF-specific macrocyclic peptide HiP-8 and the MET kinase inhibitor capmatinib in vitro. In addition, HGF-producing fibroblasts promoted entrectinib resistance in vitro (culture model) and in vivo (subcutaneous tumor model). The use of capmatinib circumvented entrectinib resistance in a subcutaneous tumor model inoculated with KM12SM and HGF-producing fibroblasts. Conclusion: Our findings suggest that growth factors in the tumor microenvironment, such as HGF, may induce resistance to entrectinib in tumors with NTRK1 or ROS1 rearrangements. Our results further suggest that optimally co-administering inhibitors of resistance-inducing growth factors may maximize the therapeutic efficacy of entrectinib.
... PTKs (protein tyrosine kinases) play an important role in cell regulation, such as mitosis, development and differentiation, tumorigenesis, angiogenesis, cell survival and apoptosis, and cell cycle control. Therefore, abnormal PTKs interfere with normal physiological functions, thus promoting the occurrence and development of diseases and even tumors (100,107). FGFRs, VFGFRs, and PDGFRs are members of the PTK superfamily, and their protein structures are similar to those containing the extracellular ligand-binding domain, the transmembrane domain, and the intracellular tyrosine kinase domain. Their tyrosine kinase domains are highly similar, especially their ATP binding sites (103). ...
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EMS(8p11 myeloproliferative syndrome, EMS) is an aggressive hematological neoplasm with/without eosinophilia caused by a rearrangement of the FGFR1 gene at 8p11-12. It was found that all cases carry chromosome abnormalities at the molecular level, not only the previously reported chromosome translocation and insertion but also a chromosome inversion. These abnormalities produced 17 FGFR1 fusion genes, of which the most common partner genes are ZNF198 on 13q11-12 and BCR of 22q11.2. The clinical manifestations can develop into AML (acute myeloid leukemia), T-LBL (T-cell lymphoblastic lymphoma), CML (chronic myeloid leukemia), CMML (chronic monomyelocytic leukemia), or mixed phenotype acute leukemia (MPAL). Most patients are resistant to traditional chemotherapy, and a minority of patients achieve long-term clinical remission after stem cell transplantation. Recently, the therapeutic effect of targeted tyrosine kinase inhibitors (such as pemigatinib and infigratinib) in 8p11 has been confirmed in vitro and clinical trials. The TKIs may become an 8p11 treatment option as an alternative to hematopoietic stem cell transplantation, which is worthy of further study.
... Many histological subgroups of important cancer entities are, therefore, not sufficiently druggable by inhibiting genetic driver alterations. (3) Driver alterations are often referred to as the "Achilles' heel" [8] in combating the tumor, as the growth of the affected cancer tissue is usually heavily dependent on the metabolic route activated by the driver alteration, a status called oncogene addiction [9]. On the one hand, this is a very helpful property because, in principle, it should thus be possible to develop targeted therapy drugs with few side effects. ...
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The aim of our proposed concept is to find new target structures for combating cancers with unmet medical needs. This, unfortunately, still applies to the majority of the clinically most relevant tumor entities such as, for example, liver cancer, pancreatic cancer, and many others. Current target structures almost all belong to the class of oncogenic proteins caused by tumor-specific genetic alterations, such as activating mutations, gene fusions, or gene amplifications, often referred to as cancer “driver alterations” or just “drivers.” However, restoring the lost function of tumor suppressor genes (TSGs) could also be a valid approach to treating cancer. TSG-derived proteins are usually considered as control systems of cells against oncogenic properties; thus, they represent the brakes in the “car-of-life.” Restoring these tumor-defective brakes by gene therapy has not been successful so far, with a few exceptions. It can be assumed that most TSGs are not being inactivated by genetic alteration (class 1 TSGs) but rather by epigenetic silencing (class 2 TSGs or short “C2TSGs”). Reactivation of C2TSGs in cancer therapy is being addressed by the use of DNA demethylating agents and histone deacetylase inhibitors which act on the whole cancer cell genome. These epigenetic therapies have neither been particularly successful, probably because they are “shotgun” approaches that, although acting on C2TSGs, may also reactivate epigenetically silenced oncogenic sequences in the genome. Thus, new strategies are needed to exploit the therapeutic potential of C2TSGs, which have also been named DNA methylation cancer driver genes or “DNAme drivers” recently. Here we present a concept for a new translational and therapeutic approach that focuses on the phenotypic imitation (“mimesis”) of proteins encoded by highly disease-relevant C2TSGs/DNAme drivers. Molecular knowledge on C2TSGs is used in two complementary approaches having the translational concept of defining mimetic drugs in common: First, a concept is presented how truncated and/or genetically engineered C2TSG proteins, consisting solely of domains with defined tumor suppressive function can be developed as biologicals. Second, a method is described for identifying small molecules that can mimic the effect of the C2TSG protein lost in the cancer cell. Both approaches should open up a new, previously untapped discovery space for anticancer drugs.
... Protein kinase inhibitors are small molecular inhibitors that prevent carcinogenesis by the dysregulation of the kinase domain [10]. Targeted therapy is bore with lesser ramifications since it only involves the signaling circuit and the tumor microenvironment of the molecule [11]. Cancer cells, especially breast cancer, have upregulation of more than one protein kinases [12]. ...
Article
Cancer malignancies require the application of advanced strategies leading to the development of novel theranostic. Quite often drugs target a variety of receptors in the cell signaling cascades that could be explored to combat aggressive tumors. Herein, two receptors that are over-expressed during the diagnosis of breast cancer are used as the primary drug targets, inclusively Glycogen Synthase kinase −3 beta (GSK-3Β) and Inhibitor of nuclear factor kappa kinase-beta (IKK-β). Dual-targeting inhibitors pave the way for a challenging pathway in the treatment of aberrant tumor progression. The present study involves the observation of similarities in the structure of the receptors, along with the designing of novel therapeutics that act on them by molecular docking followed by a pharmacokinetic screening approach. A 3D QSAR modeling study is performed to approach the functionality of the bioactive conformer molecules. Additionally, Molecular Dynamic Simulation parameters are used for the validation of the drug complexes. Already available inhibitors are used as reference compounds and a library of analogs generated for these compounds from the PubChem database has been used for in silico designing of novel inhibitors. Molecular Docking and ADME analysis narrowed down the vast library of compounds to two specific classes of chemical compounds. Molecular Dynamic simulation studies used for the selection of the novel moieties showed significant superiority in their stability studies and binding trajectories resulted in two novel molecules A6 and B3 that could inhibit the kinase receptors. The current work involves computational designing of therapeutics targeting two major oncogenic proteins.
... In this study, we have shown that the novel combination of gedatolisib and cofetuzumab pelidotin can be delivered in combination at full doses with manageable toxicity and has clinical activity in pts with heavily pretreated metastatic TNBC. While the PI3K pathway is genomically and transcriptomically aberrant in the majority of TNBCs, single-agent treatment with inhibitors of this pathway has resulted in only modest clinical activity, contrary to the theory of oncogene addiction (34,35). Transcriptome reprogramming has emerged as a common response mechanism in tumor cells when exposed to smallmolecule perturbations (36). ...
Article
Purpose: The PI3K pathway is dysregulated in the majority of triple-negative breast cancer(TNBCs), yet single agent inhibition of PI3K has been ineffective in TNBC. PI3K inhibition leads to an immediate compensatory up-regulation of the Wnt pathway. Dual targeting of both pathways is highly synergistic against TNBC models in vitro and in vivo. We initiated a Phase I clinical trial combining gedatolisib, a pan-class I isoform PI3K/mTOR inhibitor, and cofetuzumab pelidotin, an antibody-drug conjugate against the cell-surface PTK7 protein (Wnt pathway co-receptor) with an auristatin payload. Experimental design: Participants(pts) had metastatic TNBC or ER low (ER and PgR<5%, HER2-negative) breast cancer, and had received at least one prior chemotherapy for advanced disease. The primary objective was safety. Secondary endpoints included objective response(ORR), clinical benefit at 18 weeks(CB18), progression-free survival(PFS), and correlative analyses. Results: 18 pts were enrolled in 3 dose cohorts: gedatolisib 110 mg weekly + cofetuzumab pelidotin 1.4mg/kg every 3 weeks (n=4), 180mg + 1.4mg/kg (n=3), and 180mg + 2.8mg/kg (n=11). Nausea, anorexia, fatigue, and mucositis were common but rarely reached {greater than or equal to} Grade 3 severity. Myelosuppression was uncommon. ORR was 16.7% (3/18). An additional 3 pts had stable disease, of these 2 had stable disease for >18 weeks; CB18 was 27.8%. Median PFS was 2.0 months (95%CI for PFS:1.2-6.2). Pts with clinical benefit were enriched with genomic alterations in the PI3K and PTK7 pathways. Conclusions: The combination of gedatolisib + cofetuzumab pelidotin was well tolerated and demonstrated promising clinical activity. Further investigation of this drug combination in metastatic TNBC is warranted.
... Additional studies are needed to understand the stability and necessity of ISL2 depletion-mediated in vivo metabolic plasticity. However, our pharmacologic studies indicate that ISL2 depletion-mediated metabolic reprogramming may create a therapeutically exploitable phenotype, contributing to the growing list of cancer-specific ''addiction mechanisms'' due to genetic, transcriptional, or metabolic reprogramming (Weinstein and Joe, 2006;Bradner et al., 2017). ...
Article
Pancreatic ductal adenocarcinoma (PDA) cells reprogram their transcriptional and metabolic programs to survive the nutrient-poor tumor microenvironment. Through in vivo CRISPR screening, we discovered islet-2 (ISL2) as a candidate tumor suppressor that modulates aggressive PDA growth. Notably, ISL2, a nuclear and chromatin-associated transcription factor, is epigenetically silenced in PDA tumors and high promoter DNA methylation or its reduced expression correlates with poor patient survival. The exogenous ISL2 expression or CRISPR-mediated upregulation of the endogenous loci reduces cell proliferation. Mechanistically, ISL2 regulates the expression of metabolic genes, and its depletion increases oxidative phosphorylation (OXPHOS). As such, ISL2-depleted human PDA cells are sensitive to the inhibitors of mitochondrial complex I in vitro and in vivo. Spatial transcriptomic analysis shows heterogeneous intratumoral ISL2 expression, which correlates with the expression of critical metabolic genes. These findings nominate ISL2 as a putative tumor suppressor whose inactivation leads to increased mitochondrial metabolism that may be exploitable therapeutically.
... Activating point mutations at glycine-12, glycine-13 or glutamine-61 impair the intrinsic GTPase activity of KRAS protein and lead to its constitutive activation and persistent stimulation of the downstream signaling pathways that drive oncogenesis (6)(7)(8)(9)(10). There is growing evidence that the maintenance of the malignant phenotype depends on the constitutive expression of KRAS, a phenomenon termed 'oncogene addiction' (7,(11)(12)(13)(14). Consequently, suppression of mutated KRAS impacts the viability of pancreatic cancer cells. ...
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Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive types of cancer, is characterized by aberrant activity of oncogenic KRAS. A nuclease-hypersensitive GC-rich region in KRAS promoter can fold into a four-stranded DNA secondary structure called G-quadruplex (G4), known to regulate KRAS expression. However, the factors that regulate stable G4 formation in the genome and KRAS expression in PDAC are largely unknown. Here, we show that APE1 (apurinic/apyrimidinic endonuclease 1), a multifunctional DNA repair enzyme, is a G4-binding protein, and loss of APE1 abrogates the formation of stable G4 structures in cells. Recombinant APE1 binds to KRAS promoter G4 structure with high affinity and promotes G4 folding in vitro. Knockdown of APE1 reduces MAZ transcription factor loading onto the KRAS promoter, thus reducing KRAS expression in PDAC cells. Moreover, downregulation of APE1 sensitizes PDAC cells to chemotherapeutic drugs in vitro and in vivo. We also demonstrate that PDAC patients’ tissue samples have elevated levels of both APE1 and G4 DNA. Our findings unravel a critical role of APE1 in regulating stable G4 formation and KRAS expression in PDAC and highlight G4 structures as genomic features with potential application as a novel prognostic marker and therapeutic target in PDAC.
... In addition to guiding mechanistic interrogation, in vivo tumor suppressor restoration approaches have the potential to uncover the extent to which the maintenance of a neoplastic state depends upon the sustained inactivation of a given tumor suppressor. While the dependence on oncogene activity is well-established and supported by the clinical success of oncogene-targeted therapies, the consequences of reactivating tumor suppressors are much less understood 16,17 . Fascinatingly, studies on some of the most frequently inactivated tumor suppressors have revealed that the restoration of different tumor suppressors in vivo drives distinct phenotypic outcomes (from complete regression after Apc restoration to inhibition of metastatic progression after Rb1 restoration) [18][19][20][21][22] . ...
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LKB1 is among the most frequently altered tumor suppressors in lung adenocarcinoma. Inactivation of Lkb1 accelerates the growth and progression of oncogenic KRAS-driven lung tumors in mouse models. However, the molecular mechanisms by which LKB1 constrains lung tumorigenesis and whether the cancer state that stems from Lkb1 deficiency can be reverted remains unknown. To identify the processes governed by LKB1 in vivo, we generated an allele which enables Lkb1 inactivation at tumor initiation and subsequent Lkb1 restoration in established tumors. Restoration of Lkb1 in oncogenic KRAS-driven lung tumors suppressed proliferation and led to tumor stasis. Lkb1 restoration activated targets of C/EBP transcription factors and drove neoplastic cells from a progenitor-like state to a less proliferative alveolar type II cell-like state. We show that C/EBP transcription factors govern a subset of genes that are induced by LKB1 and depend upon NKX2-1. We also demonstrate that a defining factor of the alveolar type II lineage, C/EBPα, constrains oncogenic KRAS-driven lung tumor growth in vivo. Thus, this key tumor suppressor regulates lineage-specific transcription factors, thereby constraining lung tumor development through enforced differentiation.
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In the current study, novel pyrazolo[3,4-d]pyrimidine derivatives 5a–h were designed and synthesized as targeted anti-cancer agents through dual CDK2/GSK-3β inhibition. The designed compounds demonstrated moderate to potent activity on the evaluated cancer cell lines (MCF-7 and T-47D). Compounds 5c and 5 g showed the most promising cytotoxic activity against the tested cell lines surpassing that of the used reference standard; staurosporine. On the other hand, both compounds showed good safety and tolerability on normal fibroblast cell line (MCR5). The final compounds 5c and 5 g showed a promising dual CDK2/GSK-3β inhibitory activity with IC50 of 0.244 and 0.128 μM, respectively, against CDK2, and IC50 of 0.317 and 0.160 μM, respectively, against GSK-3β. Investigating the effect of compounds 5c and 5 g on CDK2 and GSK-3β downstream cascades showed that they reduced the relative cellular content of phosphorylated RB1 and β-catenin compared to that in the untreated MCF-7 cells. Moreover, compounds 5c and 5 g showed a reasonable selective inhibition against the target kinases CDK2/GSK-3β in comparison to a set of seven off-target kinases. Furthermore, the most potent compound 5 g caused cell cycle arrest at the S phase in MCF-7 cells preventing the cells’ progression to G2/M phase inducing cell apoptosis. Molecular docking studies showed that the final pyrazolo[3,4-d]pyrimidine derivatives have analogous binding modes in the target kinases interacting with the hinge region key amino acids. Molecular dynamics simulations confirmed the predicted binding mode by molecular docking. Moreover, in silico predictions indicated their favorable physicochemical and pharmacokinetic properties in addition to their promising cytotoxic activity.
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At least 40% of human cancers are associated with aberrant ERK pathway activity (ERKp). Inhibitors targeting various effectors within the ERKp have been developed and explored for over two decades. Conversely, a substantial body of evidence suggests that both normal human cells and, notably to a greater extent, cancer cells exhibit susceptibility to hyperactivation of ERKp. However, this vulnerability of cancer cells remains relatively unexplored. In this review, we reexamine the evidence on the selective lethality of highly elevated ERKp activity in human cancer cells of varying backgrounds. We synthesize the insights proposed for harnessing this vulnerability of ERK-associated cancers for therapeutical approaches and contextualize these insights within established pharmacological cancer-targeting models. Moreover, we compile the intriguing preclinical findings of ERK pathway agonism in diverse cancer models. Lastly, we present a conceptual framework for target discovery regarding ERKp agonism, emphasizing the utilization of mutual exclusivity among oncogenes to develop novel targeted therapies for precision oncology.
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Erythropoietin-producing hepatocellular A2 (EphA2) is a vital member of the Eph tyrosine kinase receptor family and has been associated with developmental processes. However, it is often overexpressed in tumors and correlates with cancer progression and worse prognosis due to the activation of its noncanonical signaling pathway. Throughout cancer treatment, the emergence of drug-resistant tumor cells is relatively common. Since the early 2000s, researchers have focused on understanding the role of EphA2 in promoting drug resistance in different types of cancer, as well as finding efficient and secure EphA2 inhibitors. In this review, the current knowledge regarding induced resistance by EphA2 in cancer treatment is summarized, and the types of cancer that lead to the most cancer-related deaths are highlighted. Some EphA2 inhibitors were also investigated. Regardless of whether the cancer treatment has reached a drug-resistance stage in EphA2-overexpressing tumors, once EphA2 is involved in cancer progression and aggressiveness, targeting EphA2 is a promising therapeutic strategy, especially in combination with other target-drugs for synergistic effect. For that reason, monoclonal antibodies against EphA2 and inhibitors of this receptor should be investigated for efficacy and drug toxicity.
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Ovarian clear-cell cancer is a rare subtype of epithelial ovarian cancer with unique clinical and biological features. Despite optimal cytoreductive surgery and platinum-based chemotherapy being the standard of care, most patients experience drug resistance and a poor prognosis. Therefore, novel therapeutic approaches have been developed, including immune checkpoint blockade, angiogenesis-targeted therapy, ARID1A synthetic lethal interactions, targeting hepatocyte nuclear factor 1β, and ferroptosis. Refining predictive biomarkers can lead to more personalized medicine, identifying patients who would benefit from chemotherapy, targeted therapy, or immunotherapy. Collaboration between academic research groups is crucial for developing prognostic outcomes and conducting clinical trials to advance treatment for ovarian clear-cell cancer. Immediate progress is essential, and research efforts should prioritize the development of more effective therapeutic strategies to benefit all patients.
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Cancer is a leading cause of death worldwide. Targeted therapies aimed at key oncogenic driver mutations in combination with chemotherapy and radiotherapy as well as immunotherapy have benefited cancer patients considerably. Tumor protein p53 (TP53), a crucial tumor suppressor gene encoding p53, regulates numerous downstream genes and cellular phenotypes in response to various stressors. The affected genes are involved in diverse processes, including cell cycle arrest, DNA repair, cellular senescence, metabolic homeostasis, apoptosis, and autophagy. However, accumulating recent studies have continued to reveal novel and unexpected functions of p53 in governing the fate of tumors, for example, functions in ferroptosis, immunity, the tumor microenvironment and microbiome metabolism. Among the possibilities, the evolutionary plasticity of p53 is the most controversial, partially due to the dizzying array of biological functions that have been attributed to different regulatory mechanisms of p53 signaling. Nearly 40 years after its discovery, this key tumor suppressor remains somewhat enigmatic. The intricate and diverse functions of p53 in regulating cell fate during cancer treatment are only the tip of the iceberg with respect to its equally complicated structural biology, which has been painstakingly revealed. Additionally, TP53 mutation is one of the most significant genetic alterations in cancer, contributing to rapid cancer cell growth and tumor progression. Here, we summarized recent advances that implicate altered p53 in modulating the response to various cancer therapies, including chemotherapy, radiotherapy, and immunotherapy. Furthermore, we also discussed potential strategies for targeting p53 as a therapeutic option for cancer.
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Simple Summary The Hippo pathway is crucial for regulating cell growth, organ size, and tissue regeneration. When this pathway goes awry, it can lead to uncontrolled cell growth, tumor spread, and resistance to cancer treatments. This review covers recent progress in understanding how the Hippo pathway is involved in cancer and discusses potential therapies targeting this pathway. In addition, we address ongoing debates and provide perspectives on debated topics in this field. Abstract The Hippo pathway is conserved across species. Key mammalian Hippo pathway kinases, including MST1/2 and LATS1/2, inhibit cellular growth by inactivating the TEAD coactivators, YAP, and TAZ. Extensive research has illuminated the roles of Hippo signaling in cancer, development, and regeneration. Notably, dysregulation of Hippo pathway components not only contributes to tumor growth and metastasis, but also renders tumors resistant to therapies. This review delves into recent research on YAP/TAZ-TEAD-mediated gene regulation and biological processes in cancer. We focus on several key areas: newly identified molecular patterns of YAP/TAZ activation, emerging mechanisms that contribute to metastasis and cancer therapy resistance, unexpected roles in tumor suppression, and advances in therapeutic strategies targeting this pathway. Moreover, we provide an updated view of YAP/TAZ’s biological functions, discuss ongoing controversies, and offer perspectives on specific debated topics in this rapidly evolving field.
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The Xiphophorus melanoma receptor kinase gene, xmrk , is a bona fide oncogene driving melanocyte tumorigenesis of Xiphophorus fish. When ectopically expressed in medaka, it not only induces development of several pigment cell tumor types in different strains of medaka but also induces different tumor types within the same animal, suggesting its oncogenic activity has a transcriptomic background effect. Although the central pathways that xmrk utilizes to lead to melanomagenesis are well documented, genes and genetic pathways that modulate the oncogenic effect and alter the course of disease have not been studied so far. To understand how the genetic networks between different histocytes of xmrk ‐driven tumors are composed, we isolated two types of tumors, melanoma and xanthoerythrophoroma, from the same xmrk transgenic medaka individuals, established the transcriptional profiles of both xmrk ‐driven tumors, and compared (1) genes that are co‐expressed with xmrk in both tumor types, and (2) differentially expressed genes and their associated molecular functions, between the two tumor types. Transcriptomic comparisons between the two tumor types show melanoma and xanthoerythrophoroma are characterized by transcriptional features representing varied functions, indicating distinct molecular interactions between the driving oncogene and the cell‐type‐specific transcriptomes. Melanoma tumors exhibit gene signatures that are relevant to proliferation and invasion, while xanthoerythrophoroma tumors are characterized by expression profiles related to metabolism and DNA repair. We conclude the transcriptomic backgrounds, exemplified by cell‐type‐specific genes that are downstream of xmrk effected signaling pathways, contribute the potential to change the course of tumor development and may affect overall tumor outcomes.
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Despite advances in precision oncology, cancer remains a global public health issue. In this report, proof‐of‐principle evidence is presented that a cell‐penetrable peptide (ACP52C) dissociates transcription factor CP2c complexes and induces apoptosis in most CP2c oncogene‐addicted cancer cells through transcription activity‐independent mechanisms. CP2cs dissociated from complexes directly interact with and degrade YY1, leading to apoptosis via the MDM2‐p53 pathway. The liberated CP2cs also inhibit TDP2, causing intrinsic genome‐wide DNA strand breaks and subsequent catastrophic DNA damage responses. These two mechanisms are independent of cancer driver mutations but are hindered by high MDM2 p60 expression. However, resistance to ACP52C mediated by MDM2 p60 can be sensitized by CASP2 inhibition. Additionally, derivatives of ACP52C conjugated with fatty acid alone or with a CASP2 inhibiting peptide show improved pharmacokinetics and reduced cancer burden, even in ACP52C‐resistant cancers. This study enhances the understanding of ACP52C‐induced cancer‐specific apoptosis induction and supports the use of ACP52C in anticancer drug development.
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Ovarian clear cell carcinoma is a rare subtype of epithelial ovarian cancer with unique clinicopathological features. The most common genetic aberration observed is loss of function ARID1A mutations. Advanced and recurrent ovarian clear cell carcinoma is characterized by resistance to standard-of-care cytotoxic chemotherapy and a poor prognosis. Despite the distinct molecular features of ovarian clear cell carcinoma, current treatments for this subtype of epithelial ovarian cancer are based on clinical trials which predominantly recruited patients with high grade serous ovarian carcinoma. These factors have encouraged researchers to develop novel treatment strategies specifically for ovarian clear cell carcinoma which are currently being tested in the context of clinical trials. These new treatment strategies currently focus on three key areas: immune checkpoint blockade, targeting angiogenesis, and exploiting ARID1A synthetic lethal interactions. Rational combinations of these strategies are being assessed in clinical trials. Despite the progress made in identifying new treatments for ovarian clear cell carcinoma, predictive biomarkers to better define those patients likely to respond to new treatments remain to be elucidated. Additional future challenges which may be addressed through international collaboration include the need for randomized trials in a rare disease and establishing the relative sequencing of these novel treatments.
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İnsan hücreleri endojen ve eksojen nedenlerle oluşan genomik hasarlara karşı kompleks bir DNA hasar yanıt mekanizmasına sahiptir. Hücreler, DNA hasar yanıt işlevsizliği durumunda onarılmadıklarından genom stabilitesini tehdit eden çeşitli DNA lezyonlarını biriktirmeye başlar. Yetersiz DNA hasar yanıt aktivitesi; neoplastik transformasyona, antikanser ilaç direncine ve ilgili tedaviler neticesinde oluşan ciddi yan etkilere neden olmanın yanı sıra, tedavi yanıtının tahmininde kullanılabilir bir biyogösterge veya kanser hücrelerini mevcut tedavilere karşı daha duyarlı hale getirebilecek farmakolojik bir hedef olarak da kullanılabilmektedir. Poli (ADP-riboz) (PARP) enzimleri, DNA tek zincir kırıklarının onarılması dahil birçok hücresel mekanizmada rol oynamaktadır. BRCA1/2 proteinleri ise DNA çift zincir kırıklarının homolog rekombinasyon yolağıyla tamir edilmesinde görev almaktadır. Yapılan çalışmalar, BRCA1/2 mutasyonu neticesinde homolog rekombinasyon defektif hale gelen hücrelerin PARP inhibitörlerine karşı hassasiyet kazandığı göstermiştir. BRCA1/2 ve PARP arasında tanımlanan söz konusu sentetik letal etkileşimin başarılı klinik uygulaması, araştırmacıları homolog rekombinasyon durumunu bildirecek farklı biyogöstergeleri araştırmaya ve PARP inhibitör direncinin üstesinden gelmek için diğer potansiyel sentetik letal etkileşimleri ortaya çıkarmaya yönlendirmiştir. Bu derlemede öncelikle DNA hasar yanıt yolağının mevcut durumu özetlenmiş, sonrasında HR tamir sistemi ve PARP inhibisyonu arasındaki sentetik letalite anlatılmıştır.
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Introduction Many data already suggested that cancer and IPF are underlined by a number of common pathogenic biologic pathways. However fewer data regards the interconnections, in terms of synergy or increased toxicities, of drugs used in cancer and IPF. Particularly, how the specific therapy influences the concurrent condition and prognostic factors of response in patients with both lung cancer and IPF are far to be clarified. Similarly, identification of features of IPF patients with higher risk of developing pulmonary adverse events when treated with chemotherapy, immune checkpoint inhibitors, TKIs, or radio-therapy is of primary importance in clinical practice. Areas covered We will discuss the scientific rationale, based on the extensive analysis of literature data, by consulting several databases for combining anticancer and antifibrotic treatments and for the design of novel therapeutic strategies. The role of immunotherapy in cancer aroused in IPF context will be discussed with specific interested, based on the continuously increasing role of immune checkpoint inhibition against lung tumors. Expert opinion This work will help to improve knowledge according to a multidisciplinary perspective on a rare and orphan subset of patients, as those affected by cancer and IPF which identify an unmet clinical need. A better management during each phase of disease progression will require the design innovative trials and the development of new drugs and molecules both in the oncologic and respiratory medicine pipelines.
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Although human cancers have complex genotypes and are genomically unstable, they often remain dependent on the continued presence of single-driver mutations-a phenomenon dubbed "oncogene addiction." Such dependencies have been demonstrated in mouse models, where conditional expression systems have revealed that oncogenes able to initiate cancer are often required for tumor maintenance and progression, thus validating the pathways they control as therapeutic targets. Here, we implement an integrative approach that combines genetically defined mouse models, transcriptional profiling, and a novel inducible RNAi platform to characterize cellular programs that underlie addiction to MLL-AF9-a fusion oncoprotein involved in aggressive forms of acute myeloid leukemia (AML). We show that MLL-AF9 contributes to leukemia maintenance by enforcing a Myb-coordinated program of aberrant self-renewal involving genes linked to leukemia stem cell potential and poor prognosis in human AML. Accordingly, partial and transient Myb suppression precisely phenocopies MLL-AF9 withdrawal and eradicates aggressive AML in vivo without preventing normal myelopoiesis, indicating that strategies to inhibit Myb-dependent aberrant self-renewal programs hold promise as effective and cancer-specific therapeutics. Together, our results identify Myb as a critical mediator of oncogene addiction in AML, delineate relevant Myb target genes that are amenable to pharmacologic inhibition, and establish a general approach for dissecting oncogene addiction in vivo.
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Entrectinib is a novel potent anticancer drug with poor aqueous solubility. A supersaturable self nano emulsifying drug delivery system of entrectinib is developed using a super saturation promoter. The components of the isotropic mixture of SNEDDS were selected based on solubility and emulsification study. The optimum composition was identified using phase diagrams and further optimized by mixture design. The supersaturated SNEDDS was prepared using HPMC K4M as precipitation inhibitor. The droplet of sSNEDDS ranges from 118.42 ± 1.26 to 128.34 ± 0.63 nm with PDI values ranges from 0.112 to 0.204, which is significantly smaller than that observed with plain SNEDDS. The percent transmittance of the diluted formulation was found to be 98.78 ± 0.74. The viscosity was found to be 528 ± 32 centipoises indicating the good flow ability. FTIR and DSC studies indicated the amorphization of the drug. The dissolution profile of sSNEDDS indicated the faster release of drug compared to both pure drug suspension and SNEDDS formulation. The drug release rate is directly proportional to the concentration of the drug. The drug release from the insoluble matrix is a square root of time dependent Fickian diffusion process. The formulation was found to be stable and transparent at all pH values and the percent transmittance was more than 95%. No significant difference was observed with all the samples exposed at different storage conditions. This study demonstrated the feasibility of stabilizing and improving the in-vitro performance of SNEDDS by incorporating HPMC K4M as precipitation inhibitor.
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Introduction: MET, the hepatocyte growth factor receptor is amplified in 8% of gastro-oesophageal (GO) malignancies and associated with poor prognosis. Therapeutic targeting of MET amplification and MET mutations, has the potential to improve outcomes for patients with GO cancers (GOC). Areas covered: The efficacy of MET inhibition (METi) in preclinical studies has not translated into meaningful improvements in the treatment paradigm for unselected GOC. MET amplification has been proposed as a superior modality for patient selection, however even if confirmed, frequency and duration of response to METi is limited by rapid activation of primary and secondary resistance pathways. These observations illustrate the challenges inherent in the application of precision oncology predicated on the theory of oncogenic addiction. Expert opinion: A standardised definition of MET positivity is critical to enhance patient selection. Early successes targeting the METex14 skipping mutation demonstrate the potent therapeutic effects of METi in a clearly molecularly defined cohort. There is robust preclinical rationale and early phase data supporting exploitation of immune system interaction with MET. Pragmatic investigation of rational therapeutic combinations based on molecular profiling of both primary and metastatic disease sites with sequential circulating tumour DNA analysis can inform successful clinical development of METi agents in GOC.
Thesis
L’équipe du Dr. Poyet s’intéresse à l’étude des interactions protéine-protéine (PPIs) dans le contrôle de l’apoptose et leur modulation dans le cadre de nouvelles stratégies médicamenteuses et a démontré le rôle important de la protéine AAC-11 pour le développement et la progression tumorale. AAC-11 est une protéine anti-apoptotique, surexprimée dans de nombreux tissus et cellules néoplasiques. Elle possède un rôle crucial dans la survie de ces cellules et leur sensibilité aux agents anti-cancéreux, dû à des PPIs impliquant son domaine Leucin-Zipper (LZ).Notre équipe a donc eu l’idée de concevoir des peptides pénétrants (CPPs) dérivés du domaine LZ d’AAC-11 et agissant comme inhibiteurs compétitifs de son activité. Les CPPs sont de petites séquences d’acides aminés capables de traverser la membrane plasmique des cellules pour y délivrer un cargo. Ils ont l’avantage d’être faciles à synthétiser et à modifier et surtout d’être généralement non-toxiques in vivo. Nos peptides sont constitués de deux domaines : la pénétratine (séquence de pénétration cellulaire), couplée à des portions du domaine LZ d’AAC-11. Ces peptides appelés LZDPs ont été brevetés (PCT/EP2015/053307) sur la base de la démonstration de leur activité anti-tumorale dans divers modèles de cancers, parmi lesquels le mélanome.Mon projet de thèse visait à évaluer les propriétés anti-tumorales de ces peptides dans d’autres types de cancers, en particulier le Syndrome de Sézary (SS) et les Leucémies Aigües Myéloïdes (LAMs). Les résultats obtenus dans ces pathologies ont mis en évidence un fort effet cytotoxique des peptides LZDPs vis-à-vis des cellules malignes, mais pas des cellules saines environnantes. Cette activité anti-tumorale spécifique est non seulement observée in vitro sur des lignées cellulaires, mais aussi ex vivo sur des prélèvements de patients et in vivo dans des modèles murins pré-cliniques.J’avais également pour objectif d’approfondir nos connaissances concernant le mécanisme d’action des peptides LZDPs. Les données obtenues au cours de ma thèse ont montré qu’ils agissaient en induisant une rupture de la membrane des cellules cancéreuses qui semble due à l’interaction avec un ou des partenaires exprimés uniquement à la membrane des cellules tumorales. Un de ces partenaires est la protéine PAK1, exprimée à la membrane des cellules de Sézary et des cellules leucémiques et dont la présence est nécessaire à l’activité membranolytique des peptides. PAK1 est particulièrement intéressante car elle est connue pour être impliquée dans plusieurs étapes de la tumorigénèse, et son interaction avec AAC-11 pourrait potentiellement expliquer le développement de certains cancers.Fait intéressant, nos résultats indiquent que les peptides LZDPs induisent une mort cellulaire immunogène des cellules cancéreuses. Dans des modèles murins immunocompétents, nous avons mis en évidence que cela permettait l’activation du système immunitaire. Ainsi, dans ces modèles, il est possible d’utiliser les lysats cellulaires obtenus après exposition de cellules cancéreuses aux peptides en tant que vaccins prophylactiques ou thérapeutiques.Enfin, un autre axe de ma thèse consistait à optimiser la séquence de pénétration et la séquence active des peptides dérivés d’AAC-11. D’une part, nous avons amélioré la portion LZ du peptide, en concevant des peptides plus courts, conservant les propriétés anti-tumorales du peptide original. D’autre part, nous avons construit une séquence de pénétration plus courte et plus efficace en termes de pénétration cellulaire que la pénétratine. Les peptides « seconde génération » constitués de cette séquence associée à celle du LZ d’AAC-11 possèdent des propriétés anti-tumorales comparables à celles des peptides de première génération.Forts de ces résultats, nous espérons désormais débuter un ou plusieurs essai(s) clinique(s) dans les contextes du SS et de la LAM, en collaboration avec les équipes médicales de l’hôpital St-Louis.
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Advanced malignancy in tumours represents the phenotypic endpoint of successive genetic lesions that affect the function and regulation of oncogenes and tumour-suppressor genes. The established tumour is maintained through complex and poorly understood host-tumour interactions that guide processes such as angiogenesis and immune sequestration. The many different genetic alterations that accompany tumour genesis raise questions as to whether experimental cancer-promoting mutations remain relevant during tumour maintenance. Here we show that melanoma genesis and maintenance are strictly dependent upon expression of H-RasV12G in a doxycycline-inducible H-Ras12G mouse melanoma model null for the tumour suppressor INK4a. Withdrawal of doxycycline and H-RasV12G down-regulation resulted in clinical and histological regression of primary and explanted tumours. The initial stages of regression involved marked apoptosis in the tumour cells and host-derived endothelial cells. Although the regulation of vascular endothelial growth factor (VEGF) was found to be Ras-dependent in vitro, the failure of persistent endogenous and enforced VEGF expression to sustain tumour viability indicates that the tumour-maintaining actions of activated Ras extend beyond the regulation of VEGF expression in vivo. Our results provide genetic evidence that H-RasV12G is important in both the genesis and maintenance of solid tumours.
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The targeted repair of mutant protooncogenes or the inactivation of their gene products may be a specific and effective therapy for human neoplasia. To examine this possibility, we have used the tetracycline regulatory system to generate transgenic mice that conditionally express the MYC protooncogene in hematopoietic cells. Sustained expression of the MYC transgene culminated in the formation of malignant T cell lymphomas and acute myleoid leukemias. The subsequent inactivation of the transgene caused regression of established tumors. Tumor regression was associated with rapid proliferative arrest, differentiation and apoptosis of tumor cells, and resumption of normal host hematopoiesis. We conclude that even though tumorigenesis is a multistep process, remediation of a single genetic lesion may be sufficient to reverse malignancy.
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Cyclin D1 plays an essential regulatory role in the G1 phase of the cell cycle. The cyclin D1 gene is amplified in 20-50% of squamous cell carcinomas (SCCs), and the protein is overexpressed in up to 80% of SCCs. Our hypothesis was that gene transduction of antisense (AS) cyclin D1 in human SCCs in vivo would result in tumor reduction. A cyclin D1 cDNA was inserted into an E1/E3-deficient serotype 5 adenovirus (AS cyclin D1) in an AS orientation using homologous recombination. AS cyclin D1 transduction suppressed cyclin D1 protein expression in both cultured cells and tumors. AS cyclin D1 significantly inhibited cell proliferation by both [3H]thymidine incorporation in six SCC cell lines (P = 0.01-0.001) and the conversion of tetrazolium salt to formazan in four SCC cell lines (P = 0.01-0.004). Apoptosis detected in >25% of cells in each cell line 48 h after AS cyclin D1 transduction paralleled the reduction in cyclin D1 protein. Preformed SCCs transduced with AS cyclin D1 were significantly inhibited (P = 0.002-0.005), and apoptosis was prominent in the AS cyclin D1-treated tumors, but not in tumors treated with the control vector. These data extend prior in vitro and ex vivo results and indicate that AS cyclin D1 suppresses SCC growth both in vitro and in vivo through suppression of cyclin D1 protein expression, leading to cellular apoptosis. Our findings suggest that cyclin D1 may have a role in cell survival and that cyclin D1 AS therapy may be useful as an adjunct to standard treatment for SCC.
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The multistage process of carcinogenesis involves the progressive acquisition of mutations, and epigenetic abnormalities in the expression, of multiple genes that have highly diverse functions. An important group of these genes are involved in cell cycle control. Thus, cyclin D1 is frequently overexpressed in a varety of human cancers. Cylin D1 plays a critical role in carcinogenesis because (i) overexpression enhances cell transformation and tumorigenesis, and enhances the amplification of other genes, and (ii) an antisense cyclin D1 cDNA reverts the malignant phenotype of carcinoma cells. Therefore, cyclin D1 may be a useful biomarker in molecular epidemiology studies, and inhibitors of its function may be useful in both cancer chemoprevention and therapy. We discovered a paradoxical increase in the cell cycle inhibitors protein p27(Kip1) in a subset of human cancers, and obtained evidence for homeostatic feedback loops between cyclins D1 or E and p27(Kip1). Furthermore, derivatives of HT29 colon cancer cells with increased levels of p27(Kip1) showed increased sensitivity to induction of differentiation. This may explain why decreased p27(Kip1) in a subset of human cancers is associated with a high grade (poorly differentiated) histology and poor prognosis. Agents that increase cellular levels of p27(Kip1) may, therefore, also be useful in cancer therapy. Using an antisense Rb oligonucleotide we obtained evidence that the paradoxical increase in pRb often seen in human colon cancers protects these cells from growth inhibition and apopotosis. On the basis of these, and other findings, we hypothesize that homeostatic feedback mechanisms play a critical role in multistage carcinogenesis. Furthermore, because of their bizarre circuitry, cancer cells suffer from 'gene addiction' and 'gene hypersensitivity' disorders that might be exploited in both cancer prevention and chemotherapy.
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Clinical studies with the Abl tyrosine kinase inhibitor STI-571 in chronic myeloid leukemia demonstrate that many patients with advanced stage disease respond initially but then relapse. Through biochemical and molecular analysis of clinical material, we find that drug resistance is associated with the reactivation of BCR-ABL signal transduction in all cases examined. In six of nine patients, resistance was associated with a single amino acid substitution in a threonine residue of the Abl kinase domain known to form a critical hydrogen bond with the drug. This substitution of threonine with isoleucine was sufficient to confer STI-571 resistance in a reconstitution experiment. In three patients, resistance was associated with progressiveBCR-ABL gene amplification. These studies provide evidence that genetically complex cancers retain dependence on an initial oncogenic event and suggest a strategy for identifying inhibitors of STI-571 resistance.
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The search for new methods of treating cancer, combined with advances in our understanding of carcinogenesis, molecular biology and technology, has resulted in the development of novel biologic agents with proven clinical efficacy. One such agent is trastuzumab (Herceptin), a humanized monoclonal antibody that targets the human epidermal growth factor receptor-2 (HER2). HER2 is a member of a family of receptors that interact with each other and various ligands to stimulate various intracellular signal transduction pathways involved in cell growth control. HER2 is overexpressed in 20%-30% of women with breast cancer and is associated with aggressive tumor characteristics and poor prognosis. Trastuzumab is the first humanized monoclonal antibody to be approved for therapeutic use and the first oncogene-targeted treatment with proven survival benefit in women with HER2-positive metastatic breast cancer. However, its mechanism of action has not been fully characterized and appears to be complex. This paper reviews current knowledge of the mechanism of action of trastuzumab, including HER2 protein downregulation, prevention of HER2-containing heterodimer formation, initiation of G1 arrest and induction of p27, prevention of HER2 cleavage, inhibition of angiogenesis, and induction of immune mechanisms. The significance of these mechanisms for selection of concomitant chemotherapy is also considered.
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Molecular therapeutics, targeting the underlying defects leading to cancer initiation and progression, are the “holy grail” of cancer research, translation, and therapy. This quest has taken a major leap forward with the demonstration that STI571 (Gleevec) induces clinical remissions in over 90% and molecular remissions in 10–20% of patients with IFN-refractory chronic phase chronic myelogenous leukemia (CML). The efficacy of STI571 in CML has been shown to be caused by the requirement of the bcr/abl fusion protein, unique to CML, for its initiation and progression, requiring molecular diagnostics to identify sensitive patients. A plethora of molecular therapeutics targeting signal transduction pathways are under evaluation. Despite the presence of the target in normal cells, the drugs have, in general, been remarkably nontoxic as compared with conventional chemotherapy or radiation therapy (see Fig. 1). As expected, these agents exhibit little, if any, activity in tumors where the target is not amplified or activated. Thus individualization of therapy driven by effective molecular diagnostic approaches to determine the status of the targets in patients' cancers is as essential a component of a molecular therapeutics program as is the identification and validation of new targets or the development of novel targeted drugs.
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Direct targeting of cancer cells with gene therapy has the potential to treat cancer on the basis of its molecular characteristics. But although laboratory results have been extremely encouraging, many practical obstacles need to be overcome before gene therapy can fulfil its goals in the clinic. These issues are not trivial, but seem less formidable than the challenge of killing cancers selectively and rationally--a challenge that has been successfully addressed.
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To explore the role of c-Myc in carcinogenesis, we have developed a reversible transgenic model of pancreatic beta cell oncogenesis using a switchable form of the c-Myc protein. Activation of c-Myc in adult, mature beta cells induces uniform beta cell proliferation but is accompanied by overwhelming apoptosis that rapidly erodes beta cell mass. Thus, the oncogenic potential of c-Myc in beta cells is masked by apoptosis. Upon suppression of c-Myc-induced beta cell apoptosis by coexpression of Bcl-x(L), c-Myc triggers rapid and uniform progression into angiogenic, invasive tumors. Subsequent c-Myc deactivation induces rapid regression associated with vascular degeneration and beta cell apoptosis. Our data indicate that highly complex neoplastic lesions can be both induced and maintained in vivo by a simple combination of two interlocking molecular lesions.
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Pharmacological inactivation of oncogenes is being investigated as a possible therapeutic strategy for cancer. One potential drawback is that cessation of such therapy may allow reactivation of the oncogene and tumor regrowth. We used a conditional transgenic mouse model for MYC-induced tumorigenesis to demonstrate that brief inactivation of MYC results in the sustained regression of tumors and the differentiation of osteogenic sarcoma cells into mature osteocytes. Subsequent reactivation of MYC did not restore the cells' malignant properties but instead induced apoptosis. Thus, brief MYC inactivation appears to cause epigenetic changes in tumor cells that render them insensitive to MYC-induced tumorigenesis. These results raise the possibility that transient inactivation of MYC may be an effective therapy for certain cancers.
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A series of recent studies are providing tantalizing hints of new therapeutic approaches for combating cancer. In his Perspective, [Weinstein][1] discusses new work ([ Jain et al .][2]) demonstrating that even brief inactivation of an oncogene can permanently reverse the malignant phenotype of some types of tumor. [1]: http://www.sciencemag.org/cgi/content/full/297/5578/63 [2]: http://www.sciencemag.org/cgi/content/short/297/5578/102
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Most human tumors harbor multiple genetic alterations, including dominant mutant oncogenes. It is often not clear which of these oncogenes are continuously required and which, when inactivated, may inhibit tumorigenesis. Recently, we developed a vector that mediates suppression of gene expression through RNA interference. Here, we use a retroviral version of this vector to specifically and stably inhibit expression of only the oncogenic K-RAS(V12) allele in human tumor cells. Loss of expression of K-RAS(V12) leads to loss of anchorage-independent growth and tumorigenicity. These results indicate that viral delivery of small interfering RNAs can be used for tumor-specific gene therapy to reverse the oncogenic phenotype of cancer cells.
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The targeted degradation of key regulatory proteins is an essential element of cell cycle control. The proteasome plays a central role in the degradation of such proteins and has therefore become an important therapeutic target for diseases involving cell proliferation, notably cancer. This review summarizes numerous studies demonstrating that proteasome inhibition induces apoptosis and sensitizes cancer cells to traditional tumoricidal agents both and The potent and selective proteasome inhibitor, PS-341, is particularly promising from a therapeutic perspective, and it is the only such inhibitor that has progressed to clinical trials. Preliminary data indicate that the drug is well tolerated by patients with cancer, and further trials are underway to assess the safety and efficacy of proteasome inhibition in hematologic and solid tumors, both as a monotherapy and in combination with other chemotherapeutics.
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The beta-catenin and APC genes are key components of the Wnt signaling pathway. Mutation of these genes results in increased levels of the beta-catenin protein, which is associated with enhanced cellular proliferation and the development of both colon polyps and colon cancer. Recently, a technique known as RNA interference has been successfully adapted to mammalian cells so that it is now possible to specifically decrease the expression of cellular genes after transfection of annealed small interfering 21-mer RNAs. In the current study, we used small interfering RNA (siRNA) directed against beta-catenin to determine the effects of decreasing the high constitutive levels of this protein in colon cancer cell lines with mutations in either beta-catenin or APC. Our studies demonstrate that siRNA directed against beta-catenin markedly decreased beta-catenin-dependent gene expression and inhibited cellular proliferation as reflected in the reduced growth of these colon cancer cells both in soft agar and in nude mice. These results indicate that siRNA can target specific factors whose expression is altered in malignancy and may have the potential as a therapeutic modality to treat human cancer.
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Network theory can give a useful overview of how a biological system works. But to make testable predictions, we need the details.
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Nature is the international weekly journal of science: a magazine style journal that publishes full-length research papers in all disciplines of science, as well as News and Views, reviews, news, features, commentaries, web focuses and more, covering all branches of science and how science impacts upon all aspects of society and life.
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Gene silencing by RNA interference (RNAi) in mammalian cells using small interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs) has become a valuable genetic tool. Here, we report the construction and application of a shRNA expression library targeting 9,610 human and 5,563 mouse genes. This library is presently composed of about 28,000 sequence-verified shRNA expression cassettes contained within multi-functional vectors, which permit shRNA cassettes to be packaged in retroviruses, tracked in mixed cell populations by means of DNA 'bar codes', and shuttled to customized vectors by bacterial mating. In order to validate the library, we used a genetic screen designed to report defects in human proteasome function. Our results suggest that our large-scale RNAi library can be used in specific, genetic applications in mammals, and will become a valuable resource for gene analysis and discovery.
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Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown. We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells. Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib.
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The ubiquitin-proteasome pathway plays a central role in the targeted destruction of cellular proteins, including cell cycle regulatory proteins. Because these pathways are critical for the proliferation and survival of all cells, and in particular cancerous cells, proteasome inhibition is a potentially attractive anticancer therapy. Based on encouraging cytotoxic activity, bortezomib was the first proteasome inhibitor to be evaluated in clinical trials. Efficacy and safety results from a phase 2 clinical trial contributed to approval of bortezomib for use in patients with relapsed and refractory multiple myeloma who have received at least 2 prior therapies and have demonstrated disease progression on their last therapy.
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Gefitinib (Iressa, Astra Zeneca Pharmaceuticals) is a tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR) and induces dramatic clinical responses in nonsmall cell lung cancers (NSCLCs) with activating mutations within the EGFR kinase domain. We report that these mutant EGFRs selectively activate Akt and signal transduction and activator of transcription (STAT) signaling pathways, which promote cell survival, but have no effect on extracellular signal–regulated kinase signaling, which induces proliferation. NSCLC cells expressing mutant EGFRs underwent extensive apoptosis after small interfering RNA–mediated knockdown of the mutant EGFR or treatment with pharmacological inhibitors of Akt and STAT signaling and were relatively resistant to apoptosis induced by conventional chemotherapeutic drugs. Thus, mutant EGFRs selectively transduce survival signals on which NSCLCs become dependent; inhibition of those signals by gefitinib may contribute to the drug's efficacy.