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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.
Highlights
Ovarian cancer is the second most common gynecologic malignancy, and the number one cause of death among all gynecologic malignancies [1]
These data suggest that the combination treatment increased inhibition of cell growth, and viability, whereas cell proliferation was already fully www.oncotarget.com blocked by mTOR complex 1 (mTORC1)/2 inhibition alone with INK128
Our investigation was focused on potentiating the anti-tumor effect of dual mTORC1/2 inhibitors with cytotoxic DNA damage chemotherapy and understanding the molecular mechanism by which the chemo-sensitizing synergistic effect of mTORC1/2 inhibition occurs
Summary
Ovarian cancer is the second most common gynecologic malignancy, and the number one cause of death among all gynecologic malignancies [1]. Platinum-based chemotherapy is the standard of care for ovarian cancer. While excellent in response initially, most patients relapse with platinum-resistant disease, and approximately 25% of patients acquire de novo resistance during primary treatment or relapse within 6 months [reviewed in 3]. There www.oncotarget.com are no truly effective options for women with platinum resistant disease. Recent research and analysis of ovarian cancer genomic alterations derived from the Cancer Genome Atlas (TCGA) project call attention to the need for new molecular targets by which treatment responses can be improved in the recurrent, platinum-resistant setting [4,5,6]
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