BAP1 loss augments sensitivity to BET inhibitors in cancer cells

The tumor suppressor gene BAP1 encodes a widely expressed deubiquitinase for histone H2A. Both hereditary and acquired mutations are associated with multiple cancer types, including cutaneous melanoma (CM), uveal melanoma (UM), and clear cell renal cell carcinoma (ccRCC). However, there is no personalized therapy for BAP1-mutant cancers. Here, we describe an epigenetic drug library screening to identify small molecules that exert selective cytotoxicity against BAP1 knockout CM cells over their isogenic parental cells. Hit characterization reveals that BAP1 loss renders cells more vulnerable to bromodomain and extraterminal (BET) inhibitor-induced transcriptional alterations, G1/G0 cell cycle arrest and apoptosis. The association of BAP1 loss with sensitivity to BET inhibitors is observed in multiple BAP1-deficient cancer cell lines generated by gene editing or derived from patient tumors as well as immunodeficient xenograft and immunocompetent allograft murine models. We demonstrate that BAP1 deubiquitinase activity reduces sensitivity to BET inhibitors. Concordantly, ectopic expression of RING1A or RING1B (H2AK119 E3 ubiquitin ligases) enhances sensitivity to BET inhibitors. The mechanistic study shows that the BET inhibitor OTX015 exerts a more potent suppressive effect on the transcription of various proliferation-related genes, especially MYC, in BAP1 knockout cells than in their isogenic parental cells, primarily by targeting BRD4. Furthermore, ectopic expression of Myc rescues the BET inhibitor-sensitizing effect induced by BAP1 loss. Our study reveals new approaches to specifically suppress BAP1-deficient cancers, including CM, UM, and ccRCC.