Systematic mapping of BCL-2 gene dependencies in cancer reveals molecular determinants of BH3 mimetic sensitivity.
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.
Duke Scholars
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- bcl-X Protein
- Sulfonamides
- RNA, Messenger
- Proto-Oncogene Proteins c-bcl-2
- Neoplasms
- Mice
- Male
- Dose-Response Relationship, Drug
- Cell Line, Tumor
- Bridged Bicyclo Compounds, Heterocyclic
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- bcl-X Protein
- Sulfonamides
- RNA, Messenger
- Proto-Oncogene Proteins c-bcl-2
- Neoplasms
- Mice
- Male
- Dose-Response Relationship, Drug
- Cell Line, Tumor
- Bridged Bicyclo Compounds, Heterocyclic