Sun Yunheng, Zhang Zhenfeng, Zhang Ke, Liu Yuxia, Shen Peiye, Cai Meichun, Jia Chenqiang, Wang Wenjing, Gu Zhuowei, Ma Pengfei, Lu Huaiwu, Guan Lei, Di Wen, Zhuang Guanglei, Yin Xia
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.
Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, China.
Am J Cancer Res. 2021 Jun 15;11(6):3021-3038. eCollection 2021.
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.
BET溴结构域抑制剂（BETi）是上皮性卵巢癌（EOC）很有前景的治疗方案。然而，早期临床试验表明，药物耐受性可能会限制其抗肿瘤疗效。在此，我们表明对JQ1耐药的EOC细胞对BET抑制产生可逆性耐药，并且仍然依赖于BRD4功能。这种不敏感性是由一种独特的非遗传机制驱动的，该机制涉及对一个预先存在的细胞亚群进行克隆选择，该亚群具有充足的乙酰化组蛋白和足够的核相分离BRD4液滴，以抵消BETi的拮抗作用。通过共同阻断BET蛋白和下游Aurora激酶的垂直联合方法被证明比单一抑制剂能实现更完全的反应。总的来说，我们的研究表明表观遗传异质性与针对染色质靶向药物的治疗耐药性有关，并提出了一种合理的策略来解决这一预期的临床困境。
