Journal
MOLECULAR CELL
Volume 78, Issue 6, Pages 1096-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2020.04.027
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Funding
- National Cancer Institute PSOC [PSOC U54 CA193461, F30 CA228208, R35 CA197623, P01 CA080111, SPORE P50 CA168504]
- Susan G. Komen Foundation
- Ludwig Center at Harvard
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BET bromodomain inhibitors (BBDIs) are candidate therapeutic agents for triple-negative breast cancer (TNBC) and other cancer types, but inherent and acquired resistance to BBDIs limits their potential clinical use. Using CRISPR and small-molecule inhibitor screens combined with comprehensive molecular profiling of BBDI response and resistance, we identified synthetic lethal interactions with BBDIs and genes that, when deleted, confer resistance. We observed synergy with regulators of cell cycle progression, YAP, AXL, and SRC signaling, and chemotherapeutic agents. We also uncovered functional similarities and differences among BRD2, BRD4, and BRD7. Although deletion of BRD2 enhances sensitivity to BBDIs, BRD7 loss leads to gain of TEAD-YAP chromatin binding and luminal features associated with BBDI resistance. Single-cell RNA-seq, ATAC-seq, and cellular barcoding analysis of BBDI responses in sensitive and resistant cell lines highlight significant heterogeneity among samples and demonstrate that BBDI resistance can be pre-existing or acquired.
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