American Association for Cancer Research
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Supplementary Table S6 from Pooled Genomic Screens Identify Anti-apoptotic Genes as Targetable Mediators of Chemotherapy Resistance in Ovarian Cancer

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posted on 2023-04-03, 16:42 authored by 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, Andrew D. Cherniack, Federica Piccioni, Ursula A. Matulonis, David D.L. Bowtell, Kristopher A. Sarosiek, Anthony Letai, Levi A. Garraway, Cory M. Johannessen, Matthew Meyerson

CRISPR-Cas9 screen enrichment analysis

Funding

Victorian Cancer Agency

National Health and Medical Research Council

SU2C

TVF

Ministerio de Economia y Competitividad

Postdoctoral Individual National Research Service

NCI

NHMRC

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ARTICLE 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 associated with chemotherapy resistance. In a CRISPR-Cas9 knockout screen, loss of BCL2L1 decreased cell survival whereas loss of proapoptotic genes promoted resistance. To dissect the role of individual anti-apoptotic proteins in HGSOC chemotherapy response, we evaluated overexpression or inhibition of BCL-2, BCL-XL, BCL-W, and MCL1 in HGSOC cell lines. Overexpression of anti-apoptotic proteins decreased apoptosis and modestly increased cell viability upon cisplatin or paclitaxel treatment. Conversely, specific inhibitors of BCL-XL, MCL1, or BCL-XL/BCL-2, but not BCL-2 alone, enhanced cell death when combined with cisplatin or paclitaxel. Anti-apoptotic protein inhibitors also sensitized HGSOC cells to the poly (ADP-ribose) polymerase inhibitor olaparib. These unbiased screens highlight anti-apoptotic proteins as mediators of chemotherapy resistance in HGSOC, and support inhibition of BCL-XL and MCL1, alone or combined with chemotherapy or targeted agents, in treatment of primary and recurrent HGSOC. Anti-apoptotic proteins modulate drug resistance in ovarian cancer, and inhibitors of BCL-XL or MCL1 promote cell death in combination with chemotherapy.

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