Format

Send to

Choose Destination
Nat Commun. 2018 Aug 29;9(1):3513. doi: 10.1038/s41467-018-05815-z.

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

Author information

1
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, 27710, USA.
2
Department of Statistics, Duke University, Durham, NC, 27710, USA.
3
Department of Biostatistics, Brown University School of Public Health, Providence, RI, 02903, USA.
4
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, 27710, USA. kris.wood@duke.edu.

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.

PMID:
30158527
PMCID:
PMC6115427
DOI:
10.1038/s41467-018-05815-z
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center