The emergence of tumor cells with certain stem-like characteristics such as high aldehyde dehydrogenase (ALDH) activity due to ALDH1A1 expression contributes to chemotherapy resistance and tumor relapse. However, clinically applicable inhibitors of ALDH activity have not been reported. There is evidence to suggest that epigenetic regulation of stem-related genes contributes to the efficacy of chemotherapy. Here we show that the bromodomain and extra-terminal (BET) inhibitor INCB57643 suppresses ALDH activity by abrogating BRD4-mediated ALDH1A1 expression through a super-enhancer element and its associated enhancer RNA. INCB57643 suppressed the outgrowth of platinum-treated ovarian cancer cells in a concentration-dependent manner. Consistently, INCB57643 synergizes with carboplatin in suppressing the growth of ovarian cancer cells with BRD4 expression, which was accompanied by induction of apoptosis. These phenotypes correlate with inhibition of ALDH1A1 expression through a super-enhancer element and additional stem-related genes, including LIF, HES1 and WNT5a in promoter regions bound by BRD4. Thus, targeting the BET protein BRD4 using small molecule BET inhibitor INCB057643 is a promising strategy for targeting ALDH activity in epithelial ovarian cancer.

Citation Format: Sergey Karakashev. The BET inhibitor INCB057643 suppresses ALDH activity by targeting the ALDH1A1 super-enhancer in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3685.