PDF(Pubmed)
Abstract：
Second-generation androgen receptor (AR) signaling inhibitors (ARSIs), such as abiraterone and enzalutamide, prolong the life of patients with castration-resistant prostate cancer (CRPC). However, patients receiving ARSIs ultimately develop resistance through various complex mechanisms, including AR mutations, constitutively active AR-splice variants (AR-Vs), and AR overexpression. Here, we characterized a novel AR pure antagonist, TAS3681, which inhibits AR transcriptional activity and downregulates AR-full length (AR-FL) and AR-Vs. TAS3681 reduced the protein levels of AR-FL and AR-Vs including AR-V7 in enzalutamide-resistant cells (SAS MDV No. 3-14), in vitro and in vivo, showing strong antitumor efficacy in an AR-V7-positive xenograft model. In AR-overexpressing VCaP (prostate cancer) cells, conversely to enzalutamide, TAS3681 effectively suppressed cell proliferation and downregulated AR expression. Importantly, TAS3681 blocked the transcriptional activity of various mutant ARs, including mutations F877L/T878A and H875Y/T878A, which confer resistance to enzalutamide, and V716M and H875Y mutations, which confer resistance to darolutamide. Our results demonstrate that TAS3681 suppresses the reactivation of AR signaling, which causes resistance to ARSIs, via a newly identified mechanism of action. Therefore, TAS3681 could be a new therapeutic option for CRPC treatment.
摘要：
第二代雄激素受体（AR）信号抑制剂（ARSI），如阿比特龙和恩扎鲁他胺，延长去势抵抗性前列腺癌（CRPC）患者的寿命。然而,接受ARSI的患者最终会通过各种复杂的机制产生耐药性，包括AR突变，组成型活性AR-剪接变体（AR-Vs），AR过度表达。这里,我们表征了一种新型的AR纯拮抗剂，TAS3681抑制AR转录活性并下调AR全长（AR-FL）和AR-Vs。TAS3681降低了恩杂鲁胺抗性细胞中AR-FL和AR-Vs（SASMDVNo.3-14),在体外和体内，在AR-V7阳性异种移植模型中显示强的抗肿瘤功效。在过表达AR的VCaP（前列腺癌）细胞中，相反，恩扎鲁他胺，TAS3681有效抑制细胞增殖并下调AR表达。重要的是,TAS3681阻断了各种突变ARs的转录活性，包括突变F877L/T878A和H875Y/T878A，赋予恩扎鲁他胺抗性，和V716M和H875Y突变，赋予达洛鲁胺抗性。我们的结果表明，TAS3681抑制AR信号的再激活，导致对ARSI的抵抗，通过新确定的作用机制。因此,TAS3681可能是CRPC治疗的一种新的治疗选择。
