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.

BET 溴结构域抑制剂 (BBDI) 是三阴性乳腺癌 (TNBC) 和其他癌症类型的候选治疗药物，但对 BBDI 的固有和获得性耐药性限制了其潜在的临床应用。使用 CRISPR 和小分子抑制剂筛选，结合 BBDI 反应和抗性的全面分子分析，我们确定了与 BBDI 和基因的合成致死相互作用，这些相互作用在删除后会赋予抗性。我们观察到细胞周期进程调节剂、YAP、AXL 和 SRC 信号传导以及化疗药物的协同作用。我们还发现了 BRD2、BRD4 和 BRD7 之间功能的相似性和差异。虽然 BRD2 的缺失增强了对 BBDI 的敏感性，但 BRD7 的缺失会导致 TEAD-YAP 染色质结合和与 BBDI 抗性相关的管腔特征的增加。对敏感和耐药细胞系中 BBDI 反应的单细胞 RNA-seq、ATAC-seq 和细胞条形码分析突出了样品之间的显着异质性，并证明 BBDI 耐药性可能是预先存在的或后天获得的。