Abstract 3380: Synthetic lethal interaction betweenARID1Amutation and BET bromodomain inhibition in ovarian clear cell carcinoma

Introduction: Current treatment for advanced stage ovarian clear cell cancer is severely hampered by a lack of effective systemic therapy options, leading to a poor outlook for these patients. Given that ARID1A is inactivated by mutation in over 50% of ovarian clear cell carcinomas, we pursued an ARID1A synthetic lethal screening strategy to identify druggable targets in OCCC. Experimental procedures: We performed synthetic lethal kinome short hairpin (shRNA) screens in a large panel (n=14) of OCCC cell lines having different ARID1A mutation status. Hit validation was performed with isogenic ARID1A ko cell line pairs and in (patient-derived) xenograft mouse models. Summary of the data: We show here that BRD2 inhibition is synthetic lethal with ARID1A mutation in ovarian clear cell cancer cells. Importantly, inhibiting the BET family of proteins, to which BRD2 belongs, with small molecules specifically inhibits proliferation of ARID1A mutated cell lines both in vitro and in ovarian clear cell cancer xenografts and patient-derived xenograft models. We demonstrate that ARID1A loss leads to upregulation of the WNT ligand WNT10B, possibly causing a WNT dependency in the ARID1A mutant lines. BET inhibitors cause a reduction in WNT10B expression and WNT target genes such as MYC, JUN and WISP1, providing a potential explanation for the observed synthetic lethal interaction with ARID1A loss. Conclusions: Our study uncovered a new synthetic lethal interaction between ARID1A mutation and BET bromodomain inhibition, suggesting a new treatment strategy for ARID1A mutant ovarian clear cell carcinomas. Citation Format: Katrien Berns, Joseph J. Caumanns, E Marielle Hijmans, Annemiek Gennissen, Bastiaan Evers, Bea A. Wisman, Gert Jan Meersema, Cor Lieftink, Roderick L. Beijersbergen, Hiroaki Itamochi, Ate G. van der Zee, Steven de Jong, Rene Bernards. Synthetic lethal interaction between ARID1A mutation and BET bromodomain inhibition in ovarian clear cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3380. doi:10.1158/1538-7445.AM2017-3380