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Ref Type Journal Article
PMID (29760405)
Authors Berns K, Caumanns JJ, Hijmans EM, Gennissen AMC, Severson TM, Evers B, Wisman GBA, Jan Meersma G, Lieftink C, Beijersbergen RL, Itamochi H, van der Zee AGJ, de Jong S, Bernards R
Title ARID1A mutation sensitizes most ovarian clear cell carcinomas to BET inhibitors.
Journal Oncogene
Vol 37
Issue 33
Date 2018 Aug
URL
Abstract Text 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. Sequencing studies revealed that ARID1A is mutated in over 50% of ovarian clear cell carcinomas. To search for a rational approach to target ovarian clear cell cancers with ARID1A mutations, we performed kinome-centered lethality screens in a large panel of ovarian clear cell carcinoma cell lines. Using the largest OCCC cell line panel established to date, we show here that BRD2 inhibition is predominantly lethal in ARID1A mutated ovarian clear cell cancer cells. Importantly, small molecule inhibitors of the BET (bromodomain and extra terminal domain) family of proteins, to which BRD2 belongs, specifically inhibit proliferation of ARID1A mutated cell lines, both in vitro and in ovarian clear cell cancer xenografts and patient-derived xenograft models. BET inhibitors cause a reduction in the expression of multiple SWI/SNF members including ARID1B, providing a potential explanation for the observed lethal interaction with ARID1A loss. Our data indicate that BET inhibition may represent a novel treatment strategy for a subset of ARID1A mutated ovarian clear cell carcinomas.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ARID1A Q1148* ovarian clear cell carcinoma predicted - sensitive JQ1 Preclinical - Pdx Actionable In a preclinical study, JQ1 inhibited tumor growth in an ovarian clear cell carcinoma patient-derived xenograft (PDX) model harboring ARID1A Q1148*, but did not inhibit growth in a model with wild-type ARID1A (PMID: 29760405). 29760405
ARID1A loss ovarian clear cell carcinoma predicted - sensitive JQ1 Preclinical - Cell culture Actionable In a preclinical study, knockout of ARID1A in ovarian clear cell carcinoma cell lines resulted in increased sensitivity to growth inhibition by JQ1 compared to cells with wild-type ARID1A in culture (PMID: 29760405). 29760405
ARID1A dec exp ovarian clear cell carcinoma predicted - sensitive Molibresib Preclinical - Cell culture Actionable In a preclinical study, knockdown of ARID1A resulted in increased sensitivity to Molibresib (GSK525762) in ovarian clear cell carcinoma cell lines in culture (PMID: 29760405). 29760405