Androgen receptor (AR) antagonists, such as enzalutamide, have had a major impact on the treatment of metastatic castration-resistant prostate cancer (CRPC). However, even with the advent of AR antagonist therapies, patients continue to develop resistance, and new strategies to combat continued AR signalling are needed. Here, we develop AR degraders using PROteolysis TArgeting Chimeric (PROTAC) technology in order to determine whether depletion of AR protein can overcome mechanisms of resistance commonly associated with current AR-targeting therapies. ARD-61 is the most potent of the AR degraders and effectively induces on-target AR degradation with a mechanism consistent with the PROTAC design. Compared to clinically-approved AR antagonists, administration of ARD-61 in vitro and in vivo results in more potent anti-proliferative, pro-apoptotic effects and attenuation of downstream AR target gene expression in prostate cancer cells. Importantly, we demonstrate that ARD-61 functions in enzalutamide-resistant model systems, characterized by diverse proposed mechanisms of resistance that include AR amplification/overexpression, AR mutation, and expression of AR splice variants, such as AR-V7. While AR degraders are unable to bind and degrade AR-V7, they continue to inhibit tumor cell growth in models overexpressing AR-V7. To further explore this, we developed several isogenic prostate cell line models in which AR-V7 is highly expressed, which also failed to influence the cell inhibitory effects of AR degraders, suggesting that AR-V7 is not a functional resistance mechanism for AR antagonism. These data provide compelling evidence that full-length AR remains a prominent oncogenic driver of prostate cancers which have developed resistance to AR antagonists and highlight the clinical potential of AR degraders for treatment of CRPC.

中文翻译：

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雄激素受体降解剂克服了在前列腺癌治疗期间形成的常见耐药机制。

雄激素受体（AR）拮抗剂，例如enzalutamide，对转移性去势抵抗性前列腺癌（CRPC）的治疗产生了重大影响。然而，即使AR拮抗剂疗法的出现，患者仍会继续产生耐药性，并且需要新的策略来对抗持续的AR信号传导。在这里，我们使用蛋白水解靶嵌合体（PROTAC）技术开发了AR降解剂，以确定AR蛋白的消耗是否可以克服目前与AR靶向疗法相关的耐药机制。ARD-61是AR降解剂中最有效的，并通过与PROTAC设计一致的机制有效诱导目标AR降解。与临床批准的AR拮抗剂相比，在体外和体内给药ARD-61可产生更有效的抗增殖药，促癌细胞凋亡效应和前列腺癌细胞下游AR靶基因表达的减弱。重要的是，我们证明ARD-61在enzalutamide耐药模型系统中发挥功能，其特征在于提出的多种耐药机制包括AR扩增/过表达，AR突变和AR剪接变体（例如AR-V7）的表达。尽管AR降解剂无法结合和降解AR-V7，但它们在过表达AR-V7的模型中继续抑制肿瘤细胞的生长。为了进一步探索这一点，我们开发了AR-V7高表达的几种同基因前列腺细胞系模型，该模型也未能影响AR降解子的细胞抑制作用，表明AR-V7不是AR拮抗的功能性耐药机制。