Synthetic Lethal and Resistance Interactions with BET Bromodomain Inhibitors in Triple-Negative Breast Cancer

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. [Display omitted] •Synthetic lethal and resistance interactions with BET inhibitors in TNBC•Multiple independent unbiased screens identify the same genes and pathways•CDK4/6 inhibitors and paclitaxel have top synergies with BET bromodomain inhibitors•Deletion of SNF/SWI complex components leads to BET inhibitor resistance Shu et al. conducted integrated comprehensive molecular profiling and functional screens to identify synthetic lethal and resistance interactions with BET bromodomain inhibitors. CDK4 and BRD2 are top synthetic lethal hits, whereas deletion of BRD7 leads to resistance because of activation of genes suppressed by BET inhibitors in sensitive cells.