Department of Pathology, University of Texas (UT) Southwestern Medical Center, Dallas, Texas, USA.
Prostate Cancer Targeted Therapy and Cancer Biomarkers Group, The Institute of Cancer Research and The Royal Marsden National Health Service (NHS) Foundation Trust, Sutton, United Kingdom.
JCI Insight. 2022 May 9;7(9):e152955. doi: 10.1172/jci.insight.152955.
The bromodomain and extraterminal (BET) family of chromatin reader proteins bind to acetylated histones and regulate gene expression. The development of BET inhibitors (BETi) has expanded our knowledge of BET protein function beyond transcriptional regulation and has ushered several prostate cancer (PCa) clinical trials. However, BETi as a single agent is not associated with antitumor activity in patients with castration-resistant prostate cancer (CRPC). We hypothesized novel combinatorial strategies are likely to enhance the efficacy of BETi. By using PCa patient-derived explants and xenograft models, we show that BETi treatment enhanced the efficacy of radiation therapy (RT) and overcame radioresistance. Mechanistically, BETi potentiated the activity of RT by blocking DNA repair. We also report a synergistic relationship between BETi and topoisomerase I (TOP1) inhibitors (TOP1i). We show that the BETi OTX015 synergized with the new class of synthetic noncamptothecin TOP1i, LMP400 (indotecan), to block tumor growth in aggressive CRPC xenograft models. Mechanistically, BETi potentiated the antitumor activity of TOP1i by disrupting replication fork stability. Longitudinal analysis of patient tumors indicated that TOP1 transcript abundance increased as patients progressed from hormone-sensitive prostate cancer to CRPC. TOP1 was highly expressed in metastatic CRPC, and its expression correlated with the expression of BET family genes. These studies open new avenues for the rational combinatorial treatment of aggressive PCa.
溴结构域和末端（BET）家族的染色质读蛋白与乙酰化组蛋白结合，并调节基因表达。BET 抑制剂（BETi）的开发扩展了我们对 BET 蛋白功能的认识，超出了转录调控的范围，并为几种前列腺癌（PCa）临床试验铺平了道路。然而，作为单一药物的 BETi 与去势抵抗性前列腺癌（CRPC）患者的抗肿瘤活性无关。我们假设新的组合策略可能会增强 BETi 的疗效。通过使用 PCa 患者来源的外植体和异种移植模型，我们表明 BETi 治疗增强了放射治疗（RT）的疗效并克服了放射抗性。从机制上讲，BETi 通过阻断 DNA 修复来增强 RT 的活性。我们还报告了 BETi 和拓扑异构酶 I（TOP1）抑制剂（TOP1i）之间的协同关系。我们表明，BETi OTX015 与新型合成非喜树碱 TOP1i LMP400（伊立替康）协同作用，阻断侵袭性 CRPC 异种移植模型中的肿瘤生长。从机制上讲，BETi 通过破坏复制叉稳定性增强了 TOP1i 的抗肿瘤活性。对患者肿瘤的纵向分析表明，TOP1 转录物丰度随着患者从激素敏感性前列腺癌发展为 CRPC 而增加。TOP1 在转移性 CRPC 中高表达，其表达与 BET 家族基因的表达相关。这些研究为侵袭性 PCa 的合理联合治疗开辟了新途径。
