Resistance to BET Inhibitor Leads to Alternative Therapeutic Vulnerabilities in Castration-Resistant Prostate Cancer
Resistance to BET Inhibitor Leads to Alternative Therapeutic Vulnerabilities in Castration-Resistant Prostate Cancer
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DOI：
10.1016/j.celrep.2018.02.011
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发表时间：
2018-02-27
期刊：
影响因子：
8.8
通讯作者：
Asangani, Irfan A.
中科院分区：
文献类型：
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作者：
Pawar, Aishwarya;Gollavilli, Paradesi Naidu;Asangani, Irfan A.
BRD 4在去势抵抗性前列腺癌（CRPC）中雄激素受体（AR）协调的转录网络中起主要作用。在CRPC的临床试验中，正在评估从染色质中置换BRD 4的几种BET抑制剂（BETi）。在这里，我们描述了获得性耐药的BETi的机制，适合CRPC的靶向治疗。BETi抗性CRPC细胞在不存在看门突变的情况下显示出对多种BETi的交叉抗性，表现出减少的染色质结合的BRD 4，并且对BRD 4降解物/敲低不太敏感，表明BRD 4独立的转录程序。转录组学分析显示，由于CDK 9介导的AR磷酸化，AR信号转导重新激活，导致对CDK 9抑制剂和Enzalutamide敏感。此外，观察到与PRC 2介导的DDR基因转录沉默相关的DNA损伤增加，导致PARP抑制剂敏感性。总的来说，我们的结果确定了BETi作为单药治疗的治疗局限性;然而，我们的BETi耐药数据表明联合治疗CRPC的独特机会。
BRD4 plays a major role in the transcription networks orchestrated by androgen receptor (AR) in castration-resistant prostate cancer (CRPC). Several BET inhibitors (BETi) that displace BRD4 from chromatin are being evaluated in clinical trials for CRPC. Here, we describe mechanisms of acquired resistance to BETi that are amenable to targeted therapies in CRPC. BETi-resistant CRPC cells displayed cross-resistance to a variety of BETi in the absence of gatekeeper mutations, exhibited reduced chromatin-bound BRD4, and were less sensitive to BRD4 degraders/knockdown, suggesting a BRD4-independent transcription program. Transcriptomic analysis revealed reactivation of AR signaling due to CDK9-mediated phosphorylation of AR, resulting in sensitivity to CDK9 inhibitors and enzalutamide. Additionally, increased DNA damage associated with PRC2-mediated transcriptional silencing of DDR genes was observed, leading to PARP inhibitor sensitivity. Collectively, our results identify the therapeutic limitation of BETi as a monotherapy; however, our BETi resistance data suggest unique opportunities for combination therapies in treating CRPC.