Journal
CELL REPORTS
Volume 24, Issue 13, Pages 3393-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.08.089
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Funding
- NIH [R35CA197583, R21CA209358, R35CA210030, R50CA211399, F31CA210592, T32CA136432]
- Leukemia and Lymphoma Society (LLS)
- LLS
- National Science Foundation (NSF)
- American Cancer Society
- Wolpoff Family Foundation
- family of Ivo Coll
- Todd J. Schwartz Memorial Fund
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Cancer cells overexpress a diversity of antiapoptotic BCL-2 family proteins, such as BCL-2, MCL-1, and BFL-1/A1, to enforce cellular immortality. Thus, intensive drug development efforts have focused on targeting this class of oncogenic proteins to overcome treatment resistance. Whereas a selective BCL-2 inhibitor has been FDA approved and several small molecule inhibitors of MCL-1 have recently entered phase I clinical testing, BFL1/A1 remains undrugged. Here, we developed a series of stapled peptide design principles to engineer a functionally selective and cell-permeable BFL-1/A1 inhibitor that is specifically cytotoxic to BFL-1/A1-dependent human cancer cells. Because cancers harbor a diversity of resistance mechanisms and typically require multi-agent treatment, we further investigated BFL-1/A1 co-dependencies by mining a genome-scale CRISPR-Cas9 screen. We identified ataxia-telangiectasia-mutated (ATM) kinase as a BFL-1/A1 co-dependency in acute myeloid leukemia (AML), which informed the validation of BFL-1/A1 and ATM inhibitor co-treatment as a synergistic approach to subverting apoptotic resistance in cancer.
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