Oncotarget

Priority Research Papers:

mTORC1/2 inhibition re-sensitizes platinum-resistant ovarian cancer by disrupting selective translation of DNA damage and survival mRNAs

Gizelka David-West, Amanda Ernlund, Abhilash Gadi and Robert J. Schneider _

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Oncotarget. 2018; 9:33064-33076. https://doi.org/10.18632/oncotarget.25869

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Abstract

Gizelka David-West1,4,*, Amanda Ernlund2,*, Abhilash Gadi2 and Robert J. Schneider2,3

1 Division of Gynecologic Oncology, New York University School of Medicine, New York, NY, USA

2 Department of Microbiology, New York University School of Medicine, New York, NY, USA

3 Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA

4 New York Medical College, Westchester Medical Center, Hawthorne, NY, USA

* These authors have contributed equally to this work

Correspondence to:

Robert J. Schneider, email: Robert.schneider@nyumc.org

Keywords: mTOR; ovarian cancer; platinum resistance; translational regulation

Received: October 31, 2017    Accepted: July 08, 2018    Published: September 04, 2018

Abstract

Platinum resistance is a major cause of treatment failure and mortality in epithelial ovarian cancer. mTORC1/2 inhibitors, which impair mRNA translation, can re-sensitize resistant ovarian cancer cells to platinum chemotherapy but the mechanism remains poorly described. Using platinum-resistant OVCAR-3 cells treated with the selective mTORC1/2 inhibitor INK128/MLN128, we conducted genome-wide transcription and translation studies and analyzed the effect on cell proliferation, AKT-mTOR signaling and cell survival, to determine whether carboplatin resistance involves selective mRNA translational reprogramming, and whether it is sensitive to mTORC1/2 inhibition. Gene ontology and Ingenuity Pathway Analysis (IPA) were used to categorize gene expression changes into experimentally authenticated biochemical and molecular networks. We show that carboplatin resistance involves increased mTORC1/2 signaling, resulting in selective translation of mRNAs involved in DNA damage and repair responses (DDR), cell cycle and anti-apoptosis (survival) pathways. Re-sensitization of ovarian cancer cell killing by carboplatin required only modest mTORC1/2 inhibition, with downregulation of protein synthesis by only 20-30%. Genome-wide transcriptomic and translatomic analyses in OVCAR-3 cells revealed that the modest downregulation of global protein synthesis by dual mTORC1/2 inhibition is associated with greater selective inhibition of DDR, cell cycle and survival mRNA translation, which was confirmed in platinum-resistant SKOV-3 cells. These data suggest a clinical path to re-sensitize platinum resistant ovarian cancer to platinum chemotherapy through partial inhibition of mTORC1/2, resulting in selective translation inhibition of DDR and anti-apoptosis protective mRNAs.


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