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. LiangAndrew D. Cherniack, Federica Piccioni, Ursula A. Matulonis, David D.L. Bowtell, Kristopher A. Sarosiek, Anthony Letai, Levi A. Garraway, Cory M. Johannessen, Matthew Meyerson

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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.

Original languageEnglish
Pages (from-to)2281-2293
Number of pages13
JournalMolecular Cancer Research
Volume17
Issue number11
DOIs
StatePublished - 1 Jan 2019
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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