Journal article
Pooled genomic screens identify anti-apoptotic genes as targetable mediators of chemotherapy resistance in ovarian cancer
EH Stover, MB Baco, O Cohen, YY Li, EL Christie, M Bagul, A Goodale, Y Lee, S Pantel, MG Rees, G Wei, AG Presser, MK Gelbard, W Zhang, IK Zervantonakis, PD Bhola, J Ryan, JL Guerriero, J Montero, FJ Liang Show all
Molecular Cancer Research | AMER ASSOC CANCER RESEARCH | Published : 2019
Abstract
High-grade serous ovarian cancer (HGSOC) is often sensitive to initial treatment with platinum and taxane combination chemotherapy, but most patients relapse with chemotherapy- resistant disease. To systematically identify genes modulating chemotherapy response, we performed pooled functional genomic screens in HGSOC cell lines treated with cisplatin, paclitaxel, or cisplatin plus paclitaxel. Genes in the intrinsic pathway of apoptosis were among the top candidate resistance genes in both gain-of-function and loss-of-function screens. In an open reading frame overexpression screen, followed by a mini-pool secondary screen, anti-apoptotic genes including BCL2L1 (BCL-XL) and BCL2L2 (BCL-W) wer..
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Grants
Awarded by Bayer
Funding Acknowledgements
We acknowledge collaborators for helpful discussions: Joan Brugge, Dipanjan Chowdhury, Claudia Iavarone, Whitney Henry, Colles Price, Kentaro Ito, Vasanthi Viswanathan, Alex Spektor, Daniel Stover, Panagiotis Konstanti-nopoulos, Joyce Liu, Kyle Davis, Uri Ben-David, Justin Hwang; John Daley, Suzan Lazo, and the DFCI Flow Cytometry Core Facility; and members of the Garraway, Meyerson and Letai laboratories, the Broad Institute Cancer Program, and the Boston HGSOC working group. This work was supported by the KL2/Catalyst Medical Research Investigator Training award (an appointed KL2 award) from Harvard Catalyst [The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, NIH Award KL2TR001100)], Rivkin Center for Ovarian Cancer Scientific Scholar Award, American Society of Clinical Oncology Young Investigator Award, Kathryn Fox Samway Foundation, and Susan F. Smith Fellowship to E.H. Stover; Victorian Cancer Agency Early Career Seed Grant (ECSG15012) and National Health and Medical Research Council Project Grant (APP1124309) to E.L. Christie; Stand Up To Cancer (SU2C) and The V Foundation (TVF) SU2C-TVF Convergence Scholar Awards (D2015-037) and Ramon y Cajal Programme, Ministerio de Economia y Competitividad (RYC-2015-18357) to J. Montero; Ruth L. Kirschstein Postdoctoral Individual National Research Service Award F32 (F32CA180733) to J.L. Guerriero; NCI K99 (K99CA222554) to I. K. Zervantonakis; Breast Cancer Research Foundation to U.A. Matulonis; National Health and Medical Research Council of Australia Program Grant (APP1092856) andNHMRCResearch Fellowship Grant (APP1117044) to D.D. L. Bowtell; NCI Clinical and Translational Science Award U54 (1U54CA224068) and R01 (1R01CA219943) to C.M. Johannessen; NCI R35 (1R35CA197568) and an American Cancer Society Research Professorship to M. Meyerson. This work was conducted as part of the Slim Initiative for Genomic Medicine, a project funded by the Carlos Slim Foundation in Mexico.