Table 3:

BAP1 Alterations and Cancer Therapy

Tumor Phenotypes Related to BAP1-Alterations	Class of drugs that might impact BAP1 biologic effects	Comments
H2A ubiquitination mediated by BAP1 loss in uveal melanoma cells[58]	Histone deacetylase (HDAC) inhibitors	HDAC inhibitor vorinostat in phase 3 trial (placebo control arm) did not improve survival in malignant pleural mesothelioma (no selection for BAP1 alterations).[60] (NCT00128102)
EZH2 (enhancer of zeste 2 polycomb repressive complex 2) is upregulated in BAP1 deficient tumors[61,62]	EZH2 inhibitors	Two of 61 patients with malignant mesothelioma and concurrent BAP1 inactivation had a confirmed partial response with EZH2 inhibitor tazemostat.[63] (NCT02860286)
BAP1 regulates homologous recombination DNA damage repair[20]	Platinum agents	Overall survival was significantly longer for patients with malignant mesothelioma and loss-of-function mutations in BAP1 and DNA repair genes compared with patients with no such mutations who were treated with platinum chemotherapy.[65]
	PARP inhibitors	Niraparib (NCT03207347) and olaparib (NCT03531840)—ongoing Phase II studies selecting for patients with BAP1 alterations and other DNA repair gene defects.[67,68]
BAP1 alterations in mesothelioma correlate with tumor inflammation, infiltrating lymphocytes and increased PDL1 expression[6,12]	Anti-PD1/PDL1 compounds	Checkpoint blockade results in responses in ~20-30% of mesothelioma patients[52,53] Other chromatin remodeling genes similar to BAP1 have been associated with therapeutic response to Anti-PD1/PDL1 therapy.[74]
Loss of BAP1 expression in uveal melanoma shows upregulation of immunosuppressive genes[28]	Immune checkpoint inhibitors + Anti-CD38/Anti-CD74 compounds	Immune checkpoint inhibitors alone, result in 5-15% response rates in uveal melanoma.[44,47] Targeting other immunosuppressive markers such as CD38 and CD74, that are upregulated with BAP1-loss, may be viable adjuvants for immune checkpoint inhibitors.[28]
BAP1 mutations in renal cell carcinoma correlate with increased CCR5 expression and immunosuppression[70]	CCR5 inhibitors	CCR5 inhibition decreases immunosuppression and upregulates anti-tumor immunity in murine models of BAP1-mutant renal cell carcinoma.[70]