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Colorectal cancer (CRC) is one of the most common malignant tumors worldwide. Kirsten ras (K-ras) gene is considered to participate in the progression from adenoma to carcinoma of colorectal neoplasms. The correlation between K-ras mutation and the prognosis of CRC is sill controversial. This study aimed at quantitatively summarizing the evidence f...
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Context 1
... combined analysis based on 10 included studies (10 studies and 3,468 cases) showed that there was significant differences between mutated and wild-type K-ras gene in 5-year overall survival (Figure 2, OR= 0.78 and 95% CI was [0.67, 0.91]) of colorectal cancer [18][19][20][21][24][25][26][27][28][29][30] but the heterogeneity existed (P=0.002). There were no statistic significances between either Condon 12 mutation or Condon 13 mutation and wild-type K-ras gene (Figure 3, 4) in 5-year overall survival of colorectal cancer [21,28,30]. ...
Citations
... Mutant RAS genes mediate many aspects of malignant cellular transformation (Downward, 2003) and are major drivers of poor clinical prognosis and therapy failure in various types of cancer (Aredo et al., 2019;Bardelli and Siena, 2010;Rui et al., 2015;Vendramini et al., 2022). Mutant RAS proteins act as chronically active signal transducers through downstream RAF/MAPK, PI3K/AKT and RAL effector pathways (Goulding et al., 2020;Martin et al., 2011;Prior et al., 2020;Simanshu et al., 2017). ...
The expression of mutated RAS genes drives extensive transcriptome alterations. Perturbation experiments have shown that the transcriptional responses to downstream effector pathways are partially unique and non-overlapping, suggesting a modular organization of the RAS-driven expression program. However, the relationship between individual deregulated transcription factors and the entire cancer cell-specific genetic program is poorly understood. To identify potential regulators of the RAS/MAPK-dependent fraction of the genetic program, we monitored transcriptome and proteome changes following conditional, time-resolved expression of mutant HRASG12V in human epithelial cells during neoplastic conversion. High mobility group AT hook2 (HMGA2), an architectural chromatin modulating protein and oncofetal tumour marker, was recovered as the earliest upregulated transcription factor. Knock-down of HMGA2 reverted anchorage-independent growth and epithelial-mesenchymal transition not only in HRAS-transformed cells but also in an independent, KRASG12V-driven rat epithelial model. Moreover, HMGA2 silencing reverted the deregulated expression of 60% of RAS-responsive target genes. These features qualify HMGA2 as a master regulator of mutant RAS-driven expression patterns. The delayed deregulation of FOSL1, ZEB1 and other transcription factors with known oncogenic activity suggests that HMGA2 acts in concert with a network of regulatory factors to trigger full neoplastic conversion. Although transcription factors are considered difficult to drug, the central role of HMGA2 in the transcription factor network as well as its relevance for cancer prognosis has motivated attempts to block its function using small molecular weight compounds. The further development of direct HMGA2 antagonists may prove useful in cancer cells that have developed resistance to signalling chain inhibition.
... There is thus an urgent need to develop better therapeutics for this deadly cancer. Oncogenic RAS has been shown to be essential for tumor maintenance and KRAS mutation in CRC is associated with metastasis and poor prognosis (10)(11)(12)(13). ...
Colorectal cancer (CRC) is the third highest incidence cancer and a leading cause of cancer mortality worldwide. To date, chemotherapeutic treatment of advanced CRC that has metastasized has a dismayed success rate of less than 30%. Further, most (80%) sporadic CRCs are microsatellite-stable and are refractory to immune checkpoint blockade therapy. KRAS is a gatekeeper gene in colorectal tumorigenesis. Nevertheless, KRAS is ‘undruggable’ due to its structure. Thus, focus has been diverted to develop small molecule inhibitors for its downstream effector such as ERK/MAPK. Despite intense research efforts for the past few decades, no small molecule inhibitor has been in clinical use for CRC. Antibody targeting KRAS itself is an attractive alternative. We developed a transient ex vivo patient-derived matched mucosa-tumor primary culture to assess whether anti-KRAS antibody can be internalized to bind and inactivate KRAS. We showed that anti-KRAS antibody can enter live mucosa-tumor cells and specifically aggregate KRAS in the cytoplasm, thus hindering its translocation to the inner plasma membrane. The mis-localization of KRAS reduces KRAS dwelling time at the site where it tethers to activate downstream effectors. We previously showed that expression of SOX9 was KRAS-mutation-dependent and possibly a better effector than ERK in CRC. Herein, we showed that anti-KRAS antibody treated tumor cells have less intense SOX9 cytoplasmic and nuclear staining compared to untreated cells. Our results demonstrated that internalized anti-KRAS antibody inhibits KRAS function in tumor. With an efficient intracellular antibody delivery system, this can be further developed as combinatorial therapeutics for CRC and other KRAS-driven cancers.
... Some mutations are found to be related to outcomes in patients with CRC; for example, AXIN2 variations are associated with poor prognosis [9]. KRAS mutations are known to contribute to the initiation of CRC and are used as a predictive biomarker for survival in these patients [10]. ...
Background:
Colorectal cancer (CRC) is one of the commonest cancers worldwide. As conventional biomarkers cannot clearly define the heterogeneity of CRC, it is essential to establish novel prognostic models.
Methods:
For the training set, data pertaining to mutations, gene expression profiles, and clinical parameters were obtained from the Cancer Genome Atlas. Consensus clustering analysis was used to identify the CRC immune subtypes. CIBERSORT was used to analyze the immune heterogeneity across different CRC subgroups. Least absolute shrinkage and selection operator regression was used to identify the genes for constructing the immune feature-based prognostic model and to determine their coefficients.
Result:
A gene prognostic model was then constructed to predict patient outcomes; the model was then externally validated using data from the Gene Expression Omnibus. As a high-frequency somatic mutation, the titin (TTN) mutation has been identified as a risk factor for CRC. Our results demonstrated that TTN mutations have the potential to modulate the tumor microenvironment, converting it into the immunosuppressive type. In this study, we identified the immune subtypes of CRC. Based on the identified subtypes, 25 genes were selected for prognostic model construction; a prediction model was also constructed, and its prediction accuracy was tested using the validation dataset. The potential of the model in predicting immunotherapy responsiveness was then explored.
Conclusion:
TTN-mutant and TTN-wild-type CRC demonstrated different microenvironment features and prognosis. Our model provides a robust immune-related gene prognostic tool and a series of gene signatures for evaluating the immune features, cancer stemness, and prognosis of CRC.
... Metastatik KRK'da farklı populasyonlar arasında %30-40 arasında değişen bir oranda monoklonal antikor tedavilerine karşı yanıt vermeyen somatik RAS mutasyonları gözlenmektedir (10)(11)(12). Metastatik KRK'li hastalarda RAS mutasyonu saptanmamışsa (wild tip) setuksimab ve panitumumab gibi EGFR inhibitörü ilaçların standart sitotoksik kemoterapiye eklenmesiyle sağ kalım sürelerinin uzadığı; mutasyonlu hastalarda ise söz konusu ilaçlarla tedaviye yanıt olmadığı klinik çalışmalar ile kanıtlandığından, kemoterapi planı yapılırken öncelikle mutlaka RAS mutasyon analizinin yapılması önerilmektedir (13,14). ...
AMAÇ: Çalışmada yüksek bir insidansa sahip olan metastatik kolorektal kanser (mKRK) tanılı hastalardaki çeşitli klinik özelliklerin RAS (Rat Sarkom Virüs Geni) mutasyon durumları ve tedavide kullanılan monoklonal antikorlar açısından değerlendirilmesi amaçlanmıştır. GEREÇ VE YÖNTEM: Kesitsel araştırmamız bir onkoloji merkezinde 01.01.2014 - 01.01.2022 dönemini kapsayan retrospektif bir arşiv taraması olarak gerçekleştirilmiştir. Çalışmanın evrenini 18 yaşını doldurmuş, tedavi sürecinde VEGF inhitibitörü (bevasizumab) ya da EGFR inhitibitörü (setuksimab / panitumumab) monoklonal antikor ilaç uygulanan toplam 187 mKRK tanılı hasta oluşturmaktadır. Verilerin toplanmasında hasta arşiv dosyalarından ve hastane bilgi yönetim otomasyon sisteminden yararlanılmıştır. BULGULAR: RAS wild tip bireylerde ikinci en yüksek metastaz görülen organın periton, mutant bireylerde ise akciğer olduğu ve aralarındaki farkın istatistiksel olarak önemli olduğu tespit edilmiştir (p=0,003). Bireylerin tanı aşamasındaki serum karsinoembriyonik antijen (CEA) ve karbonhidrat antijeni 19-9 (CA19-9) seviyelerinin RAS wild tip hastalarda mutant olanlara göre nispeten daha düşük olduğu tespit edilmiştir. RAS wild grupta medyan sağ kalım süresinin 36 ay ve mutant grupta ise 27 ay olduğu saptanmıştır (p=0,001). SONUÇ: Çalışmada RAS mutasyonu varlığının genel sağ kalım süresine negatif yönde etkisi olduğu saptanmıştır. Diğer yandan sağ kalım süresine katkı anlamında monoklonal antikor ilaçlar arasında anlamlı bir fark olmadığı tespit edilmiştir. Ülkemizdeki mKRK’lı hastalarda RAS mutasyonları ile serum tümör biyobelirteçleri seviyeleri arasındaki ilişkilerin daha net ortaya konulabilmesi ve tedavi seçeneklerinin sağ kalım süresine katkıları konusunda çok merkezli ve geniş katılımlı çalışmalara ihtiyaç bulunmaktadır.
... RAS mutant patients had lower OS and PFS in our study. This corroborates with some known data in the metastatic and localized settings.[27][28][29][30] This may be due to the access to anti-EGFR therapies in RAS wild type patients. ...
After failure of first line FOLFOX‐bevacizumab for metastatic colorectal cancer (mCRC), adding either bevacizumab or aflibercept to second‐line FOLFIRI increases survival compared to FOLFIRI alone. In this French retrospective multicentre cohort, we included patients with a mCRC treated with either FOLFIRI‐aflibercept or FOLFIRI‐bevacizumab. The primary endpoint was overall survival (OS), and secondary endpoints were progression‐free survival (PFS), disease control rate (DCR: CR + PR + SD) and safety. We included 681 patients from 36 centers, 326 and 355 in the aflibercept and bevacizumab groups, respectively. Median age was 64.2 years and 45.2% of patients were men. Most patients had RAS‐mutated tumors (80.8%) and synchronous metastases (85.7%). After a median follow up of 31.2 months, median OS was 13.0 months (95% CI: 11.3‐14.7) and 10.4 months (95% CI: 8.8‐11.4) in the bevacizumab and aflibercept groups, respectively (P < .0001). Median PFS was 6.0 months (95% CI: 5.4‐6.5) and 5.1 months (95% CI: 4.3‐5.6) (P < .0001). After adjustment on age, PS, PFS of first line, primary tumor resection, metastasis location and RAS/BRAF status, bevacizumab was still associated with better OS (HR: 0.71, 95% CI: 0.59‐0.86, P = .0003). FOLFIRI‐bevacizumab combination was associated with longer OS and PFS, and a better tolerability, as compared to FOLFIRI‐aflibercept after progression on FOLFOX‐bevacizumab.
... K-RAS gene is a downstream signaling molecule of EGFR. When K-RAS gene is mutated, its expression is not regulated by EGFR signal, which leads to abnormal proliferation and metastasis of tumor cells, and then leads to resistance of patients to EGFR inhibitor drugs [9][10][11][12]. In recent years, with the advent of oxaliplatin and irinotecan, new modes of administration, new chemotherapy drugs, and new combination regimens, new breakthroughs have been made in the treatment of metastatic CRC, especially in the aspect of molecular targeted therapy [13,14]. ...
Colorectal cancer (CRC) is one of the most common malignant tumors with high morbidity and mortality. The early symptoms are latent, and most patients are in the middle or late stage when they are diagnosed. The best opportunity for surgery has been lost, and surgical resection has failed to achieve good results. In clinical practice, targeted therapy or chemotherapy is usually the main treatment. The mFOLFOX6 regimen is a standardized regimen for the treatment of advanced CRC. The main drugs in this regimen are oxaliplatin and 5-fluorouracil (5-FU). Patients with advanced CRC combined with standard chemotherapy regimens can achieve a higher resection rate of liver metastases in unresectable patients, which can achieve significant survival improvement. Therefore, in this study, oxaliplatin + calcium folinate + 5-Fu + mFOLFOX6 regimen was combined with cetuximab and simvastatin to treat CRC patients, and the clinical efficacy and prognosis were analyzed, as well as the prognostic factors. The results showed that the addition of simvastatin on the basis of conventional mFOLFOX6 regimen combined with cetuximab chemotherapy could effectively improve the efficacy, reduce the total incidence of adverse reactions, improve the overall survival rate, and prolong the overall survival time of patients. Pathological grade and peritoneal metastasis were the factors affecting the mean survival time of CRC patients.
... RAS mutation status is a wellknown predictive marker for anti-epidermal growth factor receptor (EGFR) antibody therapy and a prognostic marker for mCRC; however, its relationship with the efficacy of FTD/ TPI plus BEV is unclear. [21][22][23] Owing to the small number of patients in the C-TASK FORCE trial (N ¼ 25), the efficacy of this treatment according to RAS mutation status has not been fully clarified. ...
Background
Although the efficacy of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) against metastatic colorectal cancer (mCRC) has been demonstrated, little is known about its effectiveness upon disease stratification by RAS mutations. In this phase II study, we investigated the efficacy and safety profiles of FTD/TPI in mCRC according to RAS mutation status.
Patients and methods
Eligible patients were mCRC refractory or intolerant to all standard therapies other than FTD/TPI and regorafenib. Patients received 4-week cycles of treatment with FTD/TPI (35 mg/m², twice daily, days 1-5 and 8-12) and bevacizumab (5 mg/kg, days 1 and 15). The primary endpoint was disease control rate (DCR). The null hypothesis of DCR in both RAS wild-type (WT) and mutant (MUT) cohorts was 44%, assuming a one-sided significance level of 5.0%. The necessary sample size was estimated to be 49 patients (target sample size: 50 patients) for each cohort.
Results
Between January and September 2018, 102 patients were enrolled, and 97 patients fulfilled the eligibility criteria (48 in the RAS WT cohort and 49 in the RAS MUT cohort). DCRs in the RAS WT and MUT cohort were 66.7% [90% confidence interval (CI), 53.9%-77.8%, P = 0.0013] and 55.1% (90% CI, 42.4%-67.3%, P = 0.0780), respectively. The median progression-free survival (PFS) and overall survival (OS) were 3.8 and 9.3 months, respectively, in the RAS WT cohort and 3.5 and 8.4 months, respectively, in the RAS MUT cohort. The most common grade 3 or higher adverse event in both cohorts was neutropenia (46% in the RAS WT cohort and 62% in the RAS MUT cohort), without unexpected safety signals.
Conclusions
FTD/TPI plus bevacizumab showed promising activity with an acceptable safety profile for pretreated mCRC, regardless of RAS mutation status, although the efficacy outcomes tended to be better in RAS WT.
... Therefore, these results contribute to the hypothesis that a differential effect of bevacizumab maintenance in favor of RAS wild type patients might exist. One possible explanation could be that RAS wild type patients, in comparison to RAS mutant ones, have a less aggressive disease with a better prognosis that can benefit also from a less intensive maintenance [16,17]. A further explanation could be related to the different expression of pro-angiogenic factors according to (K)RAS status. ...
Background
The real impact of bevacizumab maintenance as single agent in metastatic colorectal cancer (mCRC) remains unclear. SAKK-41/06 and PRODIGE-9 failed to demonstrate the non-inferiority and superiority of bevacizumab versus no maintenance, respectively, while AIO-KRK-0207 showed the non-inferiority of maintenance bevacizumab versus bevacizumab and fluoropyrimidines for time to strategy failure.
Methods
Bibliography electronic databases (PubMed, MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials) were searched for English published clinical trials prospectively randomizing mCRC patients to receive bevacizumab maintenance or not after first-line chemotherapy plus bevacizumab. Individual patients’ data (IPD) were provided by investigators for all included trials. Primary end-points were progression-free survival (PFS) and overall survival (OS), both from the start of induction and maintenance. Univariate and multivariate analyses for PFS and OS were performed.
Results
Three phase III studies - PRODIGE-9, AIO-KRK-0207 and SAKK-41/06 – were included. Considering the different timing of randomization, IPD of patients not progressed during induction and starting maintenance phase entered the analysis. 909 patients were included, 457 (50%) received bevacizumab maintenance. Median PFS from induction start was 9.6 and 8.9 months in bevacizumab group versus no maintenance group, respectively (HR 0.78; 95%CI: 0.68-0.89; p<0.0001). Subgroups analysis for PFS showed a significant interaction according for RAS status (p=0.048), with a maintenance benefit limited to RAS wild-type patients. No difference in terms of OS was observed.
Conclusions
Despite the statistically significant PFS improvement for bevacizumab maintenance, the absolute benefit appears limited. Subgroup analysis shows a differential effect of bevacizumab maintenance in favor of RAS wild-type patients. Considering these results, maintenance therapy with fluoropyrimidine with or without bevacizumab remains the first option. Single agent bevacizumab maintenance can be considered in selected cases, such as cumulative toxicity or patient’s refusal, in particular for RAS wild-type patients.
... Histone modification is mainly divided into acetylation, methylation, phosphorylation and ubiquitylation, which becomes a dominating reason causing aberrant gene damage and is also a hallmark of human cancer development (Lippman et al. 2005). The Ras pathway has been shown to be involved and play important roles in diverse human cancers, such as colorectal cancer (Rui et al. 2015) and colon cancer (Goel et al. 2015). Furthermore, activated Ras-ERK1/2 pathway often discovered in multiple human cancers (Samatar and Poulikakos 2014). ...
Context: H3K18ac is linked to gene expression and DNA damage. Nevertheless, whether H3K18ac participates in regulating Ras-ERK1/2-affected lung cancer cell phenotypes remains unclear.
Objective: We explored the effects of H3K18ac on Ras-ERK1/2-affected lung cancer cell phenotypes.
Material and methods: NCI-H2126 cells were transfected with, pEGFP-K-RasWT and pEGFP-K-RasG12V/T35S plasmids for 48 h, and transfection with pEGFP-N1 served as a blank control. Then H3K18ac and AKT and ERK1/2 pathways-associated factors were examined. Different amounts of the H3K18Q (0.5, 1, and 2 μg) plasmids and RasG12V/T35S were co-transfected into NCI-H2126 cells, cell viability, cell colonies and migration were analyzed for exploring the biological functions of H3K18ac in NCI-H2126 cells. The ERK1/2 pathway downstream factors were detected by RT-PCR and ChIP assays. The regulatory functions of SIRT7, GCN5 and MDM2 in Ras-ERK1/2-regulated H3K18ac expression were finally uncovered.
Results: RasG12V/T35S transfection decreased the expression of H3K18ac about 2.5 times compared with the pEGFP-N1 transfection group, and activated ERK1/2 and AKT pathways. Moreover, H3K18ac reduced cell viability, colonies, migration, and altered ERK1/2 downstream transcription in NCI-H2126 cells. Additionally, SIRT7 knockdown increased H3K18ac expression and repressed cell viability, migration and the percentage of cells in S phase by about 50% compared to the control group, as well as changed ERK1/2 downstream factor expression. Besides, Ras-ERK1/2 decreased H3K18ac was linked to MDM2-regulated GCN5 degradation.
Conclusion: These observations disclosed that Ras-ERK1/2 promoted the development of lung cancer via decreasing H3K18ac through MDM2-mediated GCN5 degradation. These findings might provide a new therapeutic strategy for lung cancer.
... In particular, hyperactivated mutations of RAS oncogenes initiate and drive tumor progression in a significant subset of lung, colorectal, and pancreatic cancers. 1 Patients with oncogenic RAS mutations have poor prognosis in colorectal and pancreatic cancers. 2,3 As a result, drug delivery targeting RAS-driven tumors has been a long-standing goal for cancer therapy. 1,4 However, targeting cancers with RAS mutations has been a significant challenge due to the poor therapeutic index of existing RAS inhibitors. 1 Consequently, approaches that enhance delivery and accumulation of RAS-targeting therapeutics would greatly advance and significantly improve patient outcomes. ...
Background
The RAS family of oncogenes (KRAS, HRAS, NRAS) are the most frequent mutations in cancers and regulate key signaling pathways that drive tumor progression. As a result, drug delivery targeting RAS-driven tumors has been a long-standing challenge in cancer therapy. Mutant RAS activates cancer cells to actively take up nutrients, including glucose, lipids, and albumin, via macropinocytosis to fulfill their energetic requirements to survive and proliferate.
Purpose
We exploit macropinocytosis pathway to deliver nanoparticles (NPs) in cancer cells harboring activating KRAS mutations.
Methods
NPs were synthesized by the desolvation method. The physicochemical properties and stability of NPs were characterized by dynamic light scattering and transmission electron microscopy. Uptake of fluorescently labelled NPs in wild-type and mutant KRAS cells were quantitively determined by flow cytometry and qualitatively by fluorescent microscopy. NP uptake by KRAS-driven macropinocytosis was confirmed by pharmacological inhibition and genetic knockdown.
Results
We have synthesized stable albumin NPs that demonstrate significantly greater uptake in cancer cells with activating mutations of KRAS than monomeric albumin (ie, dissociated form of clinically used nab-paclitaxel). From pharmacological inhibition and semi-quantitative fluorescent microscopy studies, these NPs exhibit significantly increased uptake in mutant KRAS cancer cells than wild-type KRAS cells by macropinocytosis.
Conclusions
The uptake of albumin nanoparticles is driven by KRAS. This NP-based strategy targeting RAS-driven macropinocytosis is a facile approach toward improved delivery into KRAS-driven cancers.
