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

  • Am J Cancer Res. 2021 Jun 15;11(6):3021-3038.
Yunheng Sun  1  2 ,  Zhenfeng Zhang  3 ,  Ke Zhang  4 ,  Yuxia Liu  5 ,  Peiye Shen  1  2 ,  Meichun Cai  3 ,  Chenqiang Jia  3  6 ,  Wenjing Wang  1  2 ,  Zhuowei Gu  1  2 ,  Pengfei Ma  1  2 ,  Huaiwu Lu  7 ,  Lei Guan  8 ,  Wen Di  1  2 ,  Guanglei Zhuang  1  2 ,  Xia Yin  1  2
Affiliations
  • 1. State Key Laboratory of Oncogenes and Related Genes, Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, China.
  • 2. Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, China.
  • 3. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, China.
  • 4. Department of Oncology, Rizhao People's Hospital Shandong, China.
  • 5. Scientific Research Department, Peking Union Medical College Hospital Beijing, China.
  • 6. School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University Shanghai, China.
  • 7. Department of Gynecologic Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-Sen University Guangzhou, China.
  • 8. Department of Anesthesiology, Capital Medical University, Beijing Shijitan Hospital Beijing, China.
PMID: 34249442
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.

Keywords
BET inhibitor; Ovarian cancer; drug resistance; epigenetic heterogeneity; vertical combination therapy.
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