Abstract
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.
Highlights
These authors contributed : Katrien Berns and Joseph J
We subsequently observed that PRP4FB loss was lethal in all the Ovarian clear cell carcinoma (OCCC) cell lines tested, so toxicity appeared independent of ARID1A mutation status
We identified comparable BRD2 and BRD4 protein and RNA levels across the OCCC cell line panel indicating that different sensitivities towards BRD2 knockdown cannot be explained by the BRD2 and BRD4 status of the individual cell line (Figure S4A, B, C)
Summary
These authors contributed : Katrien Berns and Joseph J. Five histological subtypes have been defined for epithelial ovarian cancers: high-grade serous, low-grade serous, clear cell, mucinous, and endometrioid [1, 2]. Each subtype has unique molecular and clinical features, all epithelial ovarian subtypes are still treated consisting of de-bulking surgery in combination with platinum-based chemotherapy. Ovarian clear cell carcinoma (OCCC), the second most common subtype, appears to have a worse prognosis than the more common high-grade serous carcinoma, suggesting that current treatments are ineffective for OCCC, especially related to a poor response to platinum-based chemotherapy. Development of OCCC has been linked to endometriosis and is characterized by a high mutation frequency of ARID1A (>50%), a subunit of the SWI/SNF chromatin remodeling complex [4, 5].
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