2. Academic Validation
  3. Epigenetic heterogeneity promotes acquired resistance to BET bromodomain inhibition in ovarian cancer

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

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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