Department of Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada.
Commun Biol. 2021 Mar 22;4(1):381. doi: 10.1038/s42003-021-01927-3.
Therapies for lethal castration-resistant prostate cancer (CRPC) are an unmet medical need. One mechanism underlying CRPC and resistance to hormonal therapies is the expression of constitutively active splice variant(s) of androgen receptor (AR-Vs) that lack its C-terminus ligand-binding domain. Transcriptional activities of AR-Vs and full-length AR reside in its N-terminal domain (NTD). Ralaniten is the only drug proven to bind AR NTD, and it showed promise of efficacy in Phase 1 trials. The peptidyl-prolyl isomerase Pin1 is frequently overexpressed in prostate cancer. Here we show that Pin1 interacted with AR NTD. The inhibition of Pin1 expression or its activity selectively reduced the transcriptional activities of full-length AR and AR-V7. Combination of Pin1 inhibitor with ralaniten promoted cell cycle arrest and had improved antitumor activity against CRPC xenografts in vivo compared to individual monotherapies. These findings support the rationale for therapy that combines a Pin1 inhibitor with ralaniten for treating CRPC.
治疗致命的去势抵抗性前列腺癌（CRPC）是未满足的医疗需求。CRPC 和对激素治疗产生耐药性的一个机制是雄激素受体（AR）的剪接变体（AR-Vs）持续表达，这些变体缺乏其 C 末端配体结合域。AR-Vs 和全长 AR 的转录活性位于其 N 端结构域（NTD）。Ralaniten 是唯一被证明能与 AR NTD 结合的药物，在 1 期临床试验中显示出有疗效的潜力。肽基脯氨酰顺反异构酶 Pin1 在前列腺癌中经常过表达。在这里，我们表明 Pin1 与 AR NTD 相互作用。抑制 Pin1 的表达或其活性选择性地降低了全长 AR 和 AR-V7 的转录活性。与单独的单药治疗相比，Pin1 抑制剂与 ralaniten 的联合使用促进了细胞周期停滞，并改善了体内针对 CRPC 异种移植瘤的抗肿瘤活性。这些发现支持了将 Pin1 抑制剂与 ralaniten 联合用于治疗 CRPC 的治疗原理。
