Epigenetic heterogeneity promotes acquired resistance to BET bromodomain inhibition in ovarian cancer

xlomafota13 shared this article with you from Inoreader Epigenetic heterogeneity promotes acquired resistance to BET bromodomain inhibition in ovarian cancer Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):3021-3038. eCollection 2021. ABSTRACT BET bromodomain inhibitors (BETi) are promising therapeutic regimens for epithelial ovarian cancer (EOC). However, early-stage clinical trials indicate that drug tolerance may limit their anti-tumor efficacy. Here, we show that JQ1-refractory EOC cells acquire reversible resistance to BET inhibition and remain dependent on BRD4 function. The insensitivity is driven by a unique non-genetic mechanism that involves clonal selection for a pre-existing cell subpopulation with ample acetylated histones and sufficient nuclear phase-separated BRD4 droplets to counteract BETi antagonism. A vertical combination approach by co-blocking BET proteins and downstream Aurora kinases proves to achieve more complete responses than single inhibitors. Collectively, our study implicates epigenetic heterogeneity in therapeutic resistance to chromatin-targeted agents and proposes a rati onal strategy to address this anticipated clinical dilemma. PMID:34249442 | PMC:PMC8263684 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.