Journal article

Pooled Genomic Screens Identify Anti-apoptotic Genes as Targetable Mediators of Chemotherapy Resistance in Ovarian Cancer

Elizabeth H Stover, Maria B Baco, Ofir Cohen, Yvonne Y Li, Elizabeth L Christie, Mukta Bagul, Amy Goodale, Yenarae Lee, Sasha Pantel, Matthew G Rees, Guo Wei, Adam G Presser, Maya K Gelbard, Weiqun Zhang, Ioannis K Zervantonakis, Patrick D Bhola, Jeremy Ryan, Jennifer L Guerriero, Joan Montero, Felice J 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) were..

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Grants

Awarded by KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst [The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, NIH]


Awarded by Victorian Cancer Agency Early Career Seed Grant


Awarded by National Health and Medical Research Council


Awarded by Stand Up To Cancer (SU2C)


Awarded by The V Foundation (TVF)


Awarded by Ramon y Cajal Programme, Ministerio de Economia y Competitividad


Awarded by Ruth L. Kirschstein Postdoctoral Individual National Research Service Award F32


Awarded by NCI


Awarded by National Health and Medical Research Council of Australia Program Grant


Awarded by NHMRC


Awarded by NCI Clinical and Translational Science


Awarded by NATIONAL CANCER INSTITUTE


Awarded by NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES


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.