Epigenetic heterogeneity promotes acquired resistance to BET bromodomain inhibition in ovarian cancer.
Year: 2021
Type: article
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 rational strategy to address this anticipated clinical dilemma.
Source: PubMed Central
Institutions: Shanghai Jiao Tong University, Renji Hospital, State Key Laboratory of Oncogene and Related Genes, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai Cancer Institute, People’s Hospital of Rizhao, Peking Union Medical College Hospital, Sun Yat-sen University, Sun Yat-sen Memorial Hospital, Capital Medical University, Beijing Shijitan Hospital
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3182238336