title: Dual mTORC1/2 Inhibition as a Novel Strategy for the Resensitization and Treatment of Platinum-Resistant Ovarian Cancer.
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.
authors.affiliation: Department Obstetrics and Gynecology, NYU School of Medicine, New York, New York.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Musa
authors.affiliation: Department of Microbiology, NYU School of Medicine, New York, New York.
authors.forename: Amandine
authors.initials: A
authors.lastname: Alard
authors.affiliation: Department Obstetrics and Gynecology, NYU School of Medicine, New York, New York.
authors.forename: Gizelka
authors.initials: G
authors.lastname: David-West
authors.affiliation: Department Obstetrics and Gynecology, NYU School of Medicine, New York, New York. NYU Cancer Institute, New York, New York.
authors.forename: John P
authors.initials: JP
authors.lastname: Curtin
authors.affiliation: Department Obstetrics and Gynecology, NYU School of Medicine, New York, New York. NYU Cancer Institute, New York, New York.
authors.forename: Stephanie V
authors.initials: SV
authors.lastname: Blank
authors.affiliation: Department of Microbiology, NYU School of Medicine, New York, New York. NYU Cancer Institute, New York, New York. Robert.schneider@nyumc.org.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schneider
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D016190:Carboplatin / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D000068338:Everolimus / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010984:Platinum / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D010984:Platinum; D000068338:Everolimus; D016190:Carboplatin; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases