ARID1A mutation sensitizes most ovarian clear cell carcinomas to BET inhibitors

Current treatment for advanced stage ovarian clear cellcancer is severely hampered by a lack of effective systemictherapy options, leading to a poor outlook for these patients. Sequencing studies revealed that ARID1Ais mutated in over 50% of ovarian clear cell carcinomas. To search for a rational approach to target ovarian clear cellcancers with ARID1Amutations, we performed kinome-centered lethalityscreens in a large panel of ovarian clear cell carcinomacell lines. Using the largest OCCC cell line panel established to date, we show here that BRD2 inhibition is predominantly lethalin ARID1Amutated ovarian clear cellcancer cells. Importantly, small molecule inhibitors of the BET ( bromodomainand extra terminal domain) family of proteins, to which BRD2 belongs, specifically inhibit proliferation of ARID1Amutated cell lines, both in vitro and in ovarian clear cellcancer xenografts and patient-derived xenograft models. BET inhibitorscause a reduction in the expression of multiple SWI/SNFmembers including ARID1B, providing a potential explanation for the observed lethalinteraction with ARID1Aloss. Our data indicate that BET inhibition may represent a novel treatment strategy for a subset of ARID1Amutated ovarian clear cell carcinomas.