Abstract:
:There is considerable interest in the clinical development of inhibitors of mTOR complexes mTORC1 and 2. Because mTORC1 and its downstream mRNA translation effectors may protect against genotoxic DNA damage, we investigated the inhibition of mTORC1 and mTORC1/2 in the ability to reverse platinum resistance in tissue culture and in animal tumor models of serous ovarian cancer. Cell survival, tumor growth, PI3K-AKT-mTOR pathway signaling, DNA damage and repair response (DDR) gene expression, and translational control were all investigated. We show that platinum-resistant OVCAR-3 ovarian cancer cells are resensitized to low levels of carboplatin in culture by mTOR inhibition, demonstrating reduced survival after treatment with either mTORC1 inhibitor everolimus or mTORC1/2 inhibitor PP242. Platinum resistance is shown to be associated with activating phosphorylation of AKT and CHK1, inactivating phosphorylation of 4E-BP1, the negative regulator of eIF4E, which promotes increased cap-dependent mRNA translation and increased levels of CHK1 and BRCA1 proteins. Animals with platinum-resistant OVCAR-3 tumors treated with carboplatin plus mTORC1/2 inhibition had significantly longer median survival and strikingly reduced metastasis compared with animals treated with carboplatin plus everolimus, which inhibits only mTORC1. Reduced tumor growth, metastasis, and increased survival by mTORC1/2 inhibition with carboplatin treatment was associated with reduced AKT-activating phosphorylation and increased 4E-BP1 hypophosphorylation (activation). We conclude that mTORC1/2 inhibition is superior to mTORC1 inhibition in reversing platinum resistance in tumors and strongly impairs AKT activation, DNA repair responses, and translation, promoting improved survival in the background of platinum resistance. Mol Cancer Ther; 15(7); 1557-67. ©2016 AACR.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Musa F,Alard A,David-West G,Curtin JP,Blank SV,Schneider RJdoi
10.1158/1535-7163.MCT-15-0926subject
Has Abstractpub_date
2016-07-01 00:00:00pages
1557-67issue
7eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-15-0926journal_volume
15pub_type
杂志文章abstract::This study aims to explore whether E545K, the most common hotspot mutation of PIK3CA in cervical cancer, confers radioresistance to cervical cancer cells, to demonstrate the underling mechanism, and to develop the effective targets. SiHa and MS751 cells with PIK3CA-WT and PIK3CA-E545K were established by lentiviral tr...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-19-0309
更新日期:2020-02-01 00:00:00
abstract::Antibody-drug conjugates (ADC) represent a promising therapeutic modality for managing cancer. Here, we report a novel humanized ADC that targets the tetraspanin-like protein TM4SF1. TM4SF1 is highly expressed on the plasma membranes of many human cancer cells and also on the endothelial cells lining tumor blood vesse...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-15-0188
更新日期:2015-08-01 00:00:00
abstract::The androgen receptor (AR) is a key driver and therapeutic target in androgen-sensitive prostate cancer, castration-resistant prostate cancer (CRPC), and CRPC resistant to abiraterone and enzalutamide, two second-generation inhibitors of AR signaling. Because current AR inhibitors target a functioning C-terminal ligan...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-18-0432
更新日期:2019-01-01 00:00:00
abstract::Ewing's sarcoma is a pediatric cancer of the bone that is characterized by the expression of the chimeric transcription factor EWS-FLI1 that confers a highly malignant phenotype and results from the chromosomal translocation t(11;22)(q24;q12). Poor overall survival and pronounced long-term side effects associated with...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-11-0100
更新日期:2011-10-01 00:00:00
abstract::This meeting report on the fourth Fabisch Symposium for Cancer Research and Molecular Biology describes the aims of the international meeting, the main topics of the presentations, and the highlights of the conference. The fourth Fabisch Symposium was the second on Targeted Tumor Therapies and held from April 1-3, 200...
journal_title:Molecular cancer therapeutics
pub_type:
doi:10.1158/1535-7163.MCT-09-0491
更新日期:2010-01-01 00:00:00
abstract::SJG-136 is a new pyrrolobenzodiazepine dimer inducing time-dependent cytotoxicity. HCT 116 cells were exposed to 50 nmol/L of SJG-136 for 1 hour or 1 nmol/L of SJG-136 for 24 hours to achieve similar levels of interstrand cross-links (ICL). The short exposure led to a rapid formation of ICLs (1 hour), early H2AX foci ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-06-0018
更新日期:2006-06-01 00:00:00
abstract::Urokinase plasminogen activator (uPA) is a tumor-specific protease highly expressed in several types of solid tumors and rarely present on normal cells under physiologic conditions. Due to its high expression on metastatic tumors, several different strategies have been used to target the urokinase system. These have m...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-06-0315
更新日期:2006-10-01 00:00:00
abstract::G-protein mutations are one of the most common mutations occurring in uveal melanoma activating the protein kinase C (PKC)/mitogen-activated protein kinase and phosphoinositide 3-kinase (PI3K)/AKT pathways. In this study, we described the effect of dual pathway inhibition in uveal melanoma harboring GNAQ and GNA11 mut...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-13-0550
更新日期:2014-05-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-14-0046-T
更新日期:2014-08-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-06-0424
更新日期:2006-12-01 00:00:00
abstract::The humanized anti-HER2 monoclonal antibody (mAb) trastuzumab (Herceptin; Genentech) effectively inhibits human epidermal growth factor receptor 2 (HER2)-positive breast tumors. However, many patients responding to treatment often develop resistance. Cross-talk between type I insulin-like growth factor receptor (IGF-I...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-13-0558
更新日期:2014-01-01 00:00:00
abstract::ErbB2 tyrosine kinase inhibitors (TKI) block tyrosine autophosphorylation and activation of the full-length transmembrane ErbB2 receptor (p185(ErbB2)). In addition to p185(ErbB2), truncated forms of ErbB2 exist in breast cancer cell lines and clinical tumors. The contribution of these truncated forms, specifically tho...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-10-0991
更新日期:2011-08-01 00:00:00
abstract::Imatinib mesylate is a potent, molecularly targeted therapy against the oncogenic tyrosine kinase BCR-ABL. Although imatinib mesylate has considerable efficacy against chronic myeloid leukemia (CML), advanced-stage CML patients frequently become refractory to this agent. The bone marrow is the predominant microenviron...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-08-0314
更新日期:2008-10-01 00:00:00
abstract::Activation of beta-catenin is a critical step in the pathogenesis of many common human cancers and is the initiating event in adenocarcinoma of the colon. Because activation of beta-catenin provides a gain-of-function, it is tempting to speculate that specific pharmacological inhibition of activated beta-catenin might...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2002-12-01 00:00:00
abstract::The number of approved antiangiogenic drugs is constantly growing and emphasizes the need for predictive biomarkers. The aim of this study was to analyze the predictive value of epidermal growth factor-like domain 7 (EGFL7) and microRNA-126 (miR126) to first-line chemotherapy combined with bevacizumab, in patients wit...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章,随机对照试验
doi:10.1158/1535-7163.MCT-14-0131
更新日期:2014-09-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2002-07-01 00:00:00
abstract::Constitutive activation of Janus kinases (JAKs) and signal transducers and activators of transcription (STAT) occurs at very high frequency in various hematopoietic malignancies and solid tumors. It has been demonstrated that the tyrosine kinase inhibitor, AG-490, selectively blocks JAK activity and completely elimina...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2002-09-01 00:00:00
abstract::Marine invertebrates, algae, and microorganisms are prolific producers of novel secondary metabolites. Some of these secondary metabolites have the potential to be developed as chemotherapeutic agents for the treatment of a wide variety of diseases, including cancer. We describe here the mechanism leading to apoptosis...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-06-0760
更新日期:2007-09-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-16-0553
更新日期:2017-04-01 00:00:00
abstract::Spongistatin 1, a marine experimental substance with chemotherapeutic potential, induces apoptosis and inhibits clonogenic survival of MCF-7 cells. Regarding the apoptotic signaling pathways of spongistatin 1, we present two major facts. Firstly, spongistatin 1-induced cell death, mainly caspase-independent, involves ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-08-1179
更新日期:2009-10-01 00:00:00
abstract::Androgen deprivation therapy and second-generation androgen receptor signaling inhibitors such as enzalutamide are standard treatments for advanced/metastatic prostate cancer. Unfortunately, most men develop resistance and relapse; signaling via insulin-like growth factor (IGF) has been implicated in castration-resist...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-19-0378
更新日期:2020-04-01 00:00:00
abstract::We previously reported that angiotensin II type 1 receptor (AT1R) antagonists enhanced the cytotoxity of cis-dichlorodiammineplatinum (CDDP) in a bladder cancer xenograft model. To elucidate the synergistic mechanism, we investigated whether reactive oxygen species (ROS) generation induced by CDDP may affect the regul...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-10-0535
更新日期:2010-11-01 00:00:00
abstract::TRC105 is an anti-endoglin antibody currently being tested in combination with VEGF inhibitors. In the phase Ib trial, 38 patients were treated with both TRC105 and bevacizumab (BEV), and improved clinical outcomes were observed, despite the fact that 30 patients (79%) were refractory to prior anti-VEGF therapy. Plasm...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-17-0916
更新日期:2018-10-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-09-1009
更新日期:2010-06-01 00:00:00
abstract::Amplification of human epidermal growth factor receptor 2 (HER2) has been detected in 20% to 30% of gastric cancers and is associated with a poor outcome. Combination therapies with HER2-targeting agents and cytotoxic agents are considered a potential therapeutic option for gastric cancer with HER2 amplification. We h...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-10-0045
更新日期:2010-05-01 00:00:00
abstract::Bortezomib is highly effective in the treatment of multiple myeloma; however, emergent drug resistance is common. Consequently, we employed CRISPR targeting 19,052 human genes to identify unbiased targets that contribute to bortezomib resistance. Specifically, we engineered an RPMI8226 multiple myeloma cell line to ex...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-17-0130
更新日期:2017-12-01 00:00:00
abstract::Germ cell tumors (GCT) are malignant tumors that arise from pluripotent embryonic germ cells and occur in children and young adults. GCTs are treated with cisplatin-based regimens which, while overall effective, fail to cure all patients and cause significant adverse late effects. The seminoma and nonseminoma forms of...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-17-0137
更新日期:2018-05-01 00:00:00
abstract::Clinical decision making for human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is predominantly guided by disease stage and anatomic location, with few validated biomarkers. The epidermal growth factor receptor (EGFR) is an important therapeutic target, but its value in guiding therapeu...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-16-0243
更新日期:2016-10-01 00:00:00
abstract::Nanotechnology refers to the interactions of cellular and molecular components and engineered materials-typically, clusters of atoms, molecules, and molecular fragments into incredibly small particles-between 1 and 100 nm. Nanometer-sized particles have novel optical, electronic, and structural properties that are not...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章,评审
doi:10.1158/1535-7163.MCT-06-0141
更新日期:2006-08-01 00:00:00
abstract::Insulin-like growth factor-I receptor (IGF-IR) is an important mediator of tumor cell survival and shows prognostic significance in sarcoma. To explore potential therapeutic strategies for interrupting signaling through this pathway, we assessed the ability of cyclolignan picropodophyllin (PPP), a member of the cyclol...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-09-0115
更新日期:2009-08-01 00:00:00