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Molecular Cancer Therapeutics

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Small Molecule Therapeutics

Dual mTORC1/2 Inhibition as a Novel Strategy for the Resensitization and Treatment of Platinum-Resistant Ovarian Cancer

Fernanda Musa, Amandine Alard, Gizelka David-West, John P. Curtin, Stephanie V. Blank and Robert J. Schneider
Fernanda Musa
Department Obstetrics and Gynecology, NYU School of Medicine, New York, New York.
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Amandine Alard
Department of Microbiology, NYU School of Medicine, New York, New York.
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Gizelka David-West
Department Obstetrics and Gynecology, NYU School of Medicine, New York, New York.
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John P. Curtin
Department Obstetrics and Gynecology, NYU School of Medicine, New York, New York.NYU Cancer Institute, New York, New York.
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Stephanie V. Blank
Department Obstetrics and Gynecology, NYU School of Medicine, New York, New York.NYU Cancer Institute, New York, New York.
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Robert J. Schneider
Department of Microbiology, NYU School of Medicine, New York, New York.NYU Cancer Institute, New York, New York.
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  • For correspondence: Robert.schneider@nyumc.org
DOI: 10.1158/1535-7163.MCT-15-0926
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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); 1–11. ©2016 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received December 10, 2015.
  • Revision received April 12, 2016.
  • Accepted April 23, 2016.
  • ©2016 American Association for Cancer Research.
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Published OnlineFirst June 23, 2016
doi: 10.1158/1535-7163.MCT-15-0926

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Dual mTORC1/2 Inhibition as a Novel Strategy for the Resensitization and Treatment of Platinum-Resistant Ovarian Cancer
Fernanda Musa, Amandine Alard, Gizelka David-West, John P. Curtin, Stephanie V. Blank and Robert J. Schneider
Mol Cancer Ther June 23 2016 DOI: 10.1158/1535-7163.MCT-15-0926

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Dual mTORC1/2 Inhibition as a Novel Strategy for the Resensitization and Treatment of Platinum-Resistant Ovarian Cancer
Fernanda Musa, Amandine Alard, Gizelka David-West, John P. Curtin, Stephanie V. Blank and Robert J. Schneider
Mol Cancer Ther June 23 2016 DOI: 10.1158/1535-7163.MCT-15-0926
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Molecular Cancer Therapeutics
eISSN: 1538-8514
ISSN: 1535-7163

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