Systematic mapping of BCL-2 gene dependencies in cancer reveals molecular determinants of BH3 mimetic sensitivity.

Nature Communications
Ryan S SoderquistKris C Wood

Abstract

While inhibitors of BCL-2 family proteins (BH3 mimetics) have shown promise as anti-cancer agents, the various dependencies or co-dependencies of diverse cancers on BCL-2 genes remain poorly understood. Here we develop a drug screening approach to define the sensitivity of cancer cells from ten tissue types to all possible combinations of selective BCL-2, BCL-XL, and MCL-1 inhibitors and discover that most cell lines depend on at least one combination for survival. We demonstrate that expression levels of BCL-2 genes predict single mimetic sensitivity, whereas EMT status predicts synergistic dependence on BCL-XL+MCL-1. Lastly, we use a CRISPR/Cas9 screen to discover that BFL-1 and BCL-w promote resistance to all tested combinations of BCL-2, BCL-XL, and MCL-1 inhibitors. Together, these results provide a roadmap for rationally targeting BCL-2 family dependencies in diverse human cancers and motivate the development of selective BFL-1 and BCL-w inhibitors to overcome intrinsic resistance to BH3 mimetics.

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Citations

Aug 27, 2019·Journal of Cellular and Molecular Medicine·Misha MaoLinbo Wang
Mar 24, 2020·Nature Reviews. Clinical Oncology·Benedito A Carneiro, Wafik S El-Deiry
Apr 7, 2020·International Journal of Cancer. Journal International Du Cancer·Hsin-Yi TsengStuart Gallagher
Jan 29, 2020·Nature Communications·Kris C Wood
Apr 27, 2020·Apoptosis : an International Journal on Programmed Cell Death·Prashanthi Ramesh, Jan Paul Medema
Dec 14, 2018·International Journal of Molecular Sciences·Marilina García-ArandaMaximino Redondo
Feb 3, 2020·Cellular and Molecular Life Sciences : CMLS·Reza MohammadinejadIman Azimi
Sep 12, 2020·Cell Death & Disease·Ming-Jie LuoJia-Nan Gong
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Nov 9, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Justin CidadoLisa Drew
Dec 16, 2020·Cancer Cell·Mette C Kriegbaum, Krister Wennerberg
Feb 2, 2021·ACS Infectious Diseases·William NguyenBrad E Sleebs
Nov 4, 2020·Cell Death & Disease·Isha KapoorAlexandru Almasan
Dec 11, 2020·Cell Death Discovery·Surein ArulanandaW D Fairlie
Feb 19, 2021·Biochimica Et Biophysica Acta. Molecular Cell Research·Sarah Kehr, Meike Vogler
Feb 28, 2021·Cell Death & Disease·Narissa ParryMhairi Copland
Apr 4, 2021·International Journal of Molecular Sciences·Walter Douglas Fairlie, Erinna F Lee
Apr 4, 2021·Cancers·Emer O'ConnellJochen H M Prehn
Jun 13, 2021·Cell Death and Differentiation·Prashanthi RameshJan Paul Medema
May 21, 2021·American Journal of Clinical Oncology·Luke SolimanBenedito A Carneiro
Sep 14, 2021·Biochemical Society Transactions·Erinna F Lee, W Douglas Fairlie
Sep 29, 2021·Biochemical Society Transactions·W Douglas Fairlie, Erinna F Lee

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Datasets Mentioned

BETA
ABT-263

Methods Mentioned

BETA
xenograft
xenografts
PCR

Software Mentioned

GSEA
BioCarta

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