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The PI3K/AKT pathway. Main transduction signals of the PI3K pathway. Blue phospholipids indicate PIP 3 second messenger. Arrows indicate activation while bars represent inhibition. Red bars show pharmacologic targets of the pathway. Images were taken from Servier Medical Art.
Source publication
The PI3K/AKT/mTOR signaling is important for cell proliferation, survival, and metabolism. Hyperactivation of this pathway is one of the most common signaling abnormalities observed in cancer and a substantial effort has recently been made to develop molecules targeting this signaling cascade. However, it is becoming evident that PI3K inhibitors us...
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Context 1
... The proximity of these kinases allows PDK1 to phosphorylate AKT at residue T308 of the acti- vation loop (T-loop). 15,16 Subsequently, AKT is phosphorylated at residue S473 of the hydrophobic motif by the rapamycin- insensitive mTOR complex 2 (mTORC2). 17 This phosphoryla- tion is considered necessary to fully activate the kinase activity of AKT (Fig. 2); however, several reports suggest that phosphoryla- tion at the T-loop may be sufficient to engage AKT activity on selected substrates. 18,19 Activated AKT in turn phosphorylates several substrates involved in apoptosis and cell cycle regulation. For example, AKT is able to phosphorylate and inhibit Bad, a member of the Bcl -2 family, ...
Context 2
... 4, and 6, 24 which are involved in the transcriptional regulation of several genes including the proapoptotic genes CD95L, BCL2L11 (BIM), BBC3 (PUMA), and genes encoding the cell cycle inhibitors CDKN2A (p21 CIP ) and CDKN2B (p27 KIP ). In addition to these effectors, AKT can phosphorylate PRAS40 and TSC2, 2 negative regulators of mTORC1 activity (Fig. 2) 25,26 thus linking the PI3K/AKT pathway with the mTORC1 ...
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... subunit, again increasing the kinase activity of p110a. 47 Another well-studied alteration that can lead to hyperactiva- tion of the pathway is loss of function of the tumor suppressor PTEN. 51 Low PTEN phosphatase activity results in increased levels of PIP 3 and consequent activation of downstream PI3K effectors such as AKT and mTORC1 (Fig. 2). PTEN is a 55- kDa enzyme containing, among other structural motifs, a phos- phatase domain that controls the catalytic activity of the enzyme and a C2 domain that is responsible for lipid binding. 10 Somatic mutations of PTEN are found throughout the entire gene, although there is a slightly higher frequency at the R130 residue. ...
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Citations
... (versus 3.64%). This type of combination might work by inhibiting feedback activation of RTK signaling caused by the inhibition of PI3K/mTOR signaling, as demonstrated in previous studies [51,52]. Clinical trials for combinations of PI3K/mTOR signaling inhibitors and RTK agents have been launched [51,52], such as BKM120 (PI3K inhibitor) and Lapatinib (targeting EGFR and HER2) for breast cancer patients (ClinicalTrials.gov ...
... This type of combination might work by inhibiting feedback activation of RTK signaling caused by the inhibition of PI3K/mTOR signaling, as demonstrated in previous studies [51,52]. Clinical trials for combinations of PI3K/mTOR signaling inhibitors and RTK agents have been launched [51,52], such as BKM120 (PI3K inhibitor) and Lapatinib (targeting EGFR and HER2) for breast cancer patients (ClinicalTrials.gov Identifier: NCT01589861) and Erlotinib (targeting EGFR) and BKM120 for patients with advanced non-small cell lung cancer (ClinicalTrials.gov ...
Drug combination therapy is a highly effective approach for enhancing the therapeutic efficacy of anti-cancer drugs and overcoming drug resistance. However, the innumerable possible drug combinations make it impractical to screen all synergistic drug pairs. Moreover, biological insights into synergistic drug pairs are still lacking. To address this challenge, we systematically analyzed drug combination datasets curated from multiple databases to identify drug pairs more likely to show synergy. We classified drug pairs based on their MoA and discovered that 110 MoA pairs were significantly enriched in synergy in at least one type of cancer. To improve the accuracy of predicting synergistic effects of drug pairs, we developed a suite of machine learning models that achieve better predictive performance. Unlike most previous methods that were rarely validated by wet-lab experiments, our models were validated using two-dimensional cell lines and three-dimensional tumor slice culture (3D-TSC) models, implying their practical utility. Our prediction and validation results indicated that the combination of the RTK inhibitors Lapatinib and Pazopanib exhibited a strong therapeutic effect in breast cancer by blocking the downstream PI3K/AKT/mTOR signaling pathway. Furthermore, we incorporated molecular features to identify potential biomarkers for synergistic drug pairs, and almost all potential biomarkers found connections between drug targets and corresponding molecular features using protein-protein interaction network. Overall, this study provides valuable insights to complement and guide rational efforts to develop drug combination treatments.
... The phosphorylated AKT isoforms (AKT1, AKT2, and AkT3) can initiate streams of subsequent reactions relating to cell survival and cell growth. [20] AKT can promote cell survival by avoiding cell autophagy. AKT can directly phosphorylate FOXO transcription factor, where its phosphorylation prevents the expression of their tumor suppressor gene [19]. ...
Metabolic reprogramming is recognized as an essential hallmark in carcinogenesis. By investigating the cancer-specific alterations in metabolism, several common cancer phenotypes, such as accumulated somatic mutations due to gene instability, irregulated nutrient consumption, uncontrolled growth and proliferation, and aberrational mitochondrial activities, becomes the interest of study. In this article, the overall profile of cancer metabolic activities including glucose and glutamine metabolism, macromolecules synthesis, aerobic glycolysis, pentose phosphate pathways, and mitochondrial activity, as well as two important signaling pathways (PI3K/AKT/mTOR and p53) regarding cancer metabolism are discussed. During cancer progression, the proto-oncogenes are amplified, and the tumor suppressor genes are repressed due to gene instability when cancer over-proliferated. The epigenetic changes affecting cellular signaling pathways and then triggering alterations in biosynthesis and bioenergetics to support cancer growth and proliferation with sufficient building blocks and energy. The article aims to give an overview of those cancer-associated metabolisms and show a profile of cancer-related metabolites and mutated enzymes. It also highlights the interconnections between metabolic activities, the interactions between signaling pathways and cancerous metabolism, and oncometabolites and aberrational enzymes that could potentially promote carcinogenesis; hence, become therapeutic targets for treatments.
... High levels of DNA-PKcs were correlated with poor prognosis as well as an increased risk of recurrence and metastasis in patients with OS. Furthermore, the expression of this catalytic subunit was increased in MG63 cells treated with cisplatin and etoposide [78] ; the expression of DNA-PKcs in cisplatin-resistant MG-63 OS cells appears to be regulated by MARK2 via the PI3K/AKT/mTOR pathway. In this pathway, the protein most strongly associated with DNA damage repair is AKT; it has been reported that DNA damage activates AKT. ...
Osteosarcoma (OS) is the most common type of bone sarcoma. Despite the availability of multimodal treatment with surgery and chemotherapy, the clinical results remain unsatisfactory. The main reason for the poor outcomes in patients with OS is the development of resistance to methotrexate, cisplatin, doxorubicin, and ifosfamide. Molecular and cellular mechanisms associated with resistance to chemotherapy include DNA repair and cell-cycle alterations, enhanced drug efflux, increased detoxification, resistance to apoptosis, autophagy, tumor extracellular matrix, and angiogenesis. This versatility of cells to generate chemoresistance has motivated the use of anti-angiogenic therapy based on tyrosine kinase inhibitors. This approach has shown that other therapies, along with standard chemotherapy, can improve responses to therapy in patients with OS. Moreover, microRNAs may act as predictors of drug resistance in OS. This review provides insight into the molecular and cellular mechanisms involved in the development of resistance during the treatment of OS and discusses promising novel therapies (e.g., afatinib and palbociclib) for overcoming resistance to chemotherapy in OS.
... Herceptin and Gleevec are the success therapeutic agents with a high therapeutic index on PI3K/Akt pathway-dependent cancer cells as compared to normal cells. Besides, a combination of PI3K/Akt pathway inhibitors and chemotherapeutic drugs, such as combination of GDC-0941, NVP-BKM120, and XL147 with paclitaxel, can possibly result in a synergistic activity and reduced side effect [73]. ...
Diabetes mellitus (DM) is a metabolic disorder with growing global incidence, as 387 million people were diagnosed in 2014 with an expected projection of 642 million in 2040. Several complications are associated with DM including heart attack, stroke, kidney failure, blindness, and cancer. The latter is the second leading cause of death worldwide accounting for one in every six deaths, with liver, pancreas, and endometrium cancers are the most abundant among patients with diabetes. Phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway plays a vital role in developing a wide array of pathological disorders, among them diabetes and cancer. Natural secondary metabolites that counteract the deleterious effects of reactive oxygen species (ROS) and modulate PI3K/Akt/mTOR pathway could be a promising approach in cancer therapy. Here, 717 medicinal plants with antidiabetic activities were highlighted along with 357 bioactive compounds responsible for the antidiabetic activity. Also, 43 individual plant compounds with potential antidiabetic activities against cancer via the modulation of PI3K/Akt/mTOR cascade were identified. Taken together, the available data give an insight of the potential of repurposing medicinal plants and/or the individual secondary metabolites with antidiabetic activities for cancer therapy.
... Herceptin and Gleevec are the success therapeutic agents with a high therapeutic index on PI3K/Akt pathway-dependent cancer cells as compared to normal cells. Besides, a combination of PI3K/Akt pathway inhibitors and chemotherapeutic drugs, such as combination of GDC-0941, NVP-BKM120, and XL147 with paclitaxel, can possibly result in a synergistic activity and reduced side effect [73]. ...
Diabetes mellitus (DM) is a metabolic disorder with growing global incidence, as 387 million people were diagnosed in 2014 with an expected projection of 642 million in 2040. Several complications are associated with DM including heart attack, stroke, kidney failure, blindness, and cancer. The latter is the second leading cause of death worldwide accounting for one in every six deaths, with liver, pancreas, and endometrium cancers are the most abundant among patients with diabetes. Phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/ mammalian target of rapamycin (mTOR) pathway plays a vital role in developing a wide array of pathological disorders, among them diabetes and cancer. Natural secondary metabolites that counteract the deleterious effects of reactive oxygen species (ROS) and modulate PI3K/Akt/mTOR pathway could be a promising approach in cancer therapy. Here, 717 medicinal plants with antidiabetic activities were highlighted along with 357 bioactive compounds responsible for the antidiabetic activity. Also, 43 individual plant compounds with potential anti-diabetic activities against cancer via the modulation of PI3K/Akt/mTOR cascade were identified. Taken together, the available data give an insight of the potential of repurposing medicinal plants and/or the individual secondary metabolites with antidiabetic activities for cancer therapy.
... However, other attempts at combinatorial strategies with mTOR inhibitors, IGF1-R, or HER3 have been challenging to implement clinically, due to tolerance issues (42). Given the intra-and intertumoral molecular heterogeneity underlying cancer, a uniform combinatorial strategy is unlikely to be effective in all disease types, and a more systematic mapping of cancer dependencies for a given disease type and context will likely be necessary to identify optimal combinatorial strategies (43)(44)(45). ...
Purpose:
Somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA), which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), are found in multiple human cancers. While recurrent mutations in PIK3CA helical, regulatory, and kinase domains lead to constitutive PI3K pathway activation, other mutations remain uncharacterized. To further evaluate their clinical actionability, we designed a basket study for patients with PIK3CA-mutant cancers with the isoform-specific PI3K inhibitor, taselisib.
Patients and methods:
Patients were enrolled based on local PIK3CA mutation testing into 1 of 11 histology-specific cohorts and treated with taselisib at 6 mg or 4 mg daily until progression. Tumor DNA from baseline and progression (when available) was sequenced using a next-generation sequencing panel. Exploratory analyses correlating genomic alterations with treatment outcomes were performed.
Results:
166 patients with PIK3CA-mutant cancers were enrolled. The confirmed response rate was 9.0%. Activity varied by tumor type and mutant allele, with confirmed responses observed in head and neck squamous (15.4%), cervical (10.0%), and other cancers, plus tumors containing helical domain mutations. Genomic analyses identified mutations potentially associated with resistance to PI3K inhibition upfront (TP53 and PTEN) and post-progression through reactivation of the PI3K pathway (PTEN, STK11, and PIK3R1). Higher rates of dose modification occurred at higher doses of taselisib, indicating a narrow therapeutic index.
Conclusions:
Taselisib had limited activity in the tumor types tested and is no longer in development. This genome-driven study improves understanding of the activity, limitations, and resistance mechanisms of using PI3K inhibitors as monotherapy to target PIK3CA-mutant tumors.
... Arylmorpholine is the main pharmacophore. Both the hydrogen bond acceptor at the 1-position and the donor at the 2-position are required for potent DNA-PK inhibition University of California [184,185] 12. The same mechanism as AMA56 but is the most potent and selective inhibitor of DNA-PK. ...
Morpholine is a versatile moiety, a privileged pharmacophore and an outstanding heterocyclic motif with wide ranges of pharmacological activities due to different mechanisms of action. The ability of morpholine to enhance the potency of the molecule through molecular interactions with the target protein (kinases) or to modulate the pharmacokinetic properties propelled medicinal chemists and researchers to synthesize morpholine ring by the efficient ways and to incorporate this moiety to develop various lead compounds with diverse therapeutic activities. The present review primarily focused on discussing the most promising synthetic leads containing morpholine ring along with structure-activity relationship (SAR) to reveal the active pharmacophores accountable for anticancer, anti-inflammatory, antiviral, anticonvulsant, antihyperlipidemic, antioxidant, antimicrobial and antileishmanial activity. This review outlines some of the recent effective chemical synthesis for morpholine ring. The review also highlighted the metabolic liability of some clinical drugs containing this nucleus and various researches on modified morpholine to enhance the metabolic stability of drugs as well. Drugs bearing morpholine ring and those under clinical trials are also mentioned with the role of morpholine and their mechanism of action. This review will provide the necessary knowledge base to the medicinal chemists in making strategic structural changes in designing morpholine derivatives.
... with single agents [24,25]. Clinical studies have been undertaken to evaluate the effect of PI3K/AKT pathway inhibitors in combination with estrogen antagonists, aromatase inhibitors, and HER2 inhibitors [26,27]. ...
... ARQ 092 and ARQ 087 are being tested in clinical trials as single agents (NCT01473095, NCT01752920), with encouraging signs of efficacy in different cancer types. An increasingly common strategy in cancer treatment involves the combination of agents targeting different pathways or targeting the same pathway at multiple points [26,27], and as recently shown by Davies et al. [30] in endometrial and bladder tumors, there is a preclinical and clinical rationale for combining AKT and FGFR inhibitors. ...
The PI3K/AKT pathway plays an important role in the initiation and progression of cancer, and the drug development efforts targeting this pathway with therapeutic interventions have been advanced by academic and industrial groups. However, the clinical outcome is moderate. Combination of inhibition of PI3K/AKT and other targeted agents became a feasible approach. In this study we assessed the combined effect of ARQ 092, a pan-AKT inhibitor, and ARQ 087, a pan-FGFR inhibitor, in vitro and in vivo. In a panel of 45 cancer cell lines, on 24% (11 out of 45) the compounds showed synergistic effect, on 62% (28 out of 45) additive, and on 13% (6 out of 45) antagonistic. The highest percentage of synergism was found on endometrial and ovarian cancer cell lines. Mutational analysis revealed that PIK3CA/PIK3R1 mutations and aberrant activation of FGFR2 predicted synergism, whereas Ras mutations showed a reverse correlation. Pathway analysis revealed that a combination of ARQ 092 and ARQ 087 enhanced the inhibition of both the AKT and FGFR pathways in cell lines in which synergistic effects were found (AN3CA and IGROV-1). Cell cycle arrest and apoptotic response occurred only in AN3CA cell, and was not seen in IGROV-1 cells. Furthermore, enhanced antitumor activity was observed in mouse models with endometrial cancer cell line and patient-derived tumors when ARQ 092 and ARQ 087 were combined. These results from in-vitro and in-vivo studies provide a strong rationale in treating endometrial and other cancers with the activated PI3K/AKT and FGFR pathways.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/.
Poorly differentiated esophageal adenocarcinoma (PDEAC) has a dismal prognosis. Glypican-1(GPC-1) is known to be upregulated in several cancer types in contrast to healthy tissues, rendering it as a biomarker. Nevertheless, the potential therapeutic targeting of GPC-1 has not been explored in PDEAC. There is accumulating evidence that GPC-1, via upregulation of PI3K/Akt/ERK signaling, plays a crucial role in the progression and chemoresistance in cancer. Pictilisib, a class I pan PI3K inhibitor, has shown promising antitumor results in clinical trials, however, has not gained widespread success due to acquired drug resistance. This study investigated the role of GPC-1 in chemo-resistant PDEAC and appraises the impact of targeted silencing of GPC-1 on the antitumor effects of Pictilisib in PDEAC cell lines. Immunohistochemistry assays in PDEAC tissue specimens demonstrated a pronounced intensity of staining with GPC-1. Upregulation of GPC-1 was found to be correlated with advanced stage and poor prognosis. In-vitro studies examined the influence of GPC-1 knockdown and Pictilisib, both as individual agents and in combination, on cytotoxicity, cell cycle distribution, apoptosis, and gene expression profiles. Silencing GPC-1 alone showed significantly reduced cell viability, migration, colony formation, epithelial-mesenchymal transition, and stemness in PDEAC cells. Significantly, knockdown of GPC-1 combined with low-dose Pictilisib led to enhancement of cytotoxicity, cell cycle arrest, and apoptosis in ESO-26 and OE-33 cells. In the xenograft mouse model, the combination of Pictilisib and GPC-1 knockdown exhibited synergy. These findings suggest that GPC-1 represents a promising target to augment chemosensitivity in esophageal adenocarcinoma.
PI3K signaling pathway, especially PIK3CA, the gene encoding the catalytic subunit of the PI3K complex, is highly mutated and amplified in various cancer types, including non-small cell lung cancer. Although PI3K inhibitors have been used in clinics for follicular lymphoma and chronic lymphocytic leukemia, no agents targeting PI3K aberrations in lung cancer have been approved by FDA so far. In this study, we observed that the PIK3CA-mutant or amplified lung cancer cells were more sensitive to EZH2 inhibition. PIK3CA-E545K, the most common mutation in lung cancer, harbored a modest induction of stem-like properties in lung epithelial cells, and drove development of adenocarcinoma autochthonously when paired with p53 loss in a murine mouse model. EZH2 inhibitor synergized with PI3K inhibitor in human cancer cells in vitro and worked together efficiently in vivo. Mechanistically, EZH2 inhibition cooperated with PI3K inhibition to produce a more potent suppression of phospho-AKT downstream of PI3K. This study suggests a promising combination therapy to combat lung cancers with PIK3CA mutation or amplification. Both copanlisib, the PI3K inhibitor, and tazemetostat, the EZH2 inhibitor, are FDA-approved, which should enhance the clinical translation of this work.
