Armstrong Cameron M, Gao Allen C
Department of Urology, University of California, Davis, Sacramento, CA, USA.
Comprehensive Cancer Center, University of California, Davis, Sacramento, CA, USA.
Asian J Urol. 2019 Jan;6(1):42-49. doi: 10.1016/j.ajur.2018.07.003. Epub 2018 Sep 29.
Current therapies for advanced prostate cancer, such as enzalutamide and abiraterone, focus on inhibiting androgen receptor (AR) activity and reducing downstream signaling pathways to inhibit tumor growth. Unfortunately, cancer cells are very adaptable and, over time, these cells develop mechanisms by which they can circumvent therapeutics. One of the many mechanisms that have been discovered is the generation of AR variants. These variants are generated through alternative splicing of the full length AR and often lack the ligand binding domain. This leads to forms of the AR that are constitutively active that continue to promote prostate cancer cell growth even in the absence of ligand. The high prevalence of AR variants and their role in disease progression have prompted a number of studies investigating ways to inhibited AR variant expression and activity. Among these are the anti-helminthic drug, niclosamide, which selectively promotes degradation of AR variants over full length AR and re-sensitizes anti-androgen resistant prostate cancer cells to treatment with enzalutamide and abiraterone. Other AR variant targeting mechanisms include interfering with AR variant co-activators and the development of drugs that bind to the DNA or N-terminal AR domains, which are retained in most AR variants. The clinical efficacy of treating prostate cancer by targeting AR variants is under investigation in several clinical trials. In this review, we provide an overview of the most relevant AR variants and discuss current AR variant targeting strategies.
目前针对晚期前列腺癌的疗法，如恩杂鲁胺和阿比特龙，主要集中在抑制雄激素受体（AR）活性并减少下游信号通路以抑制肿瘤生长。不幸的是，癌细胞具有很强的适应性，随着时间的推移，这些细胞会形成能够规避治疗的机制。已发现的众多机制之一是AR变体的产生。这些变体是通过全长AR的可变剪接产生的，通常缺乏配体结合域。这导致了AR的组成型激活形式，即使在没有配体的情况下也能继续促进前列腺癌细胞的生长。AR变体的高发生率及其在疾病进展中的作用促使了许多研究来探索抑制AR变体表达和活性的方法。其中包括抗蠕虫药物氯硝柳胺，它能选择性地促进AR变体而非全长AR的降解，并使抗雄激素耐药的前列腺癌细胞重新对恩杂鲁胺和阿比特龙治疗敏感。其他针对AR变体的机制包括干扰AR变体共激活因子以及开发与DNA或N端AR结构域结合的药物，这些结构域在大多数AR变体中都保留着。通过靶向AR变体治疗前列腺癌的临床疗效正在多项临床试验中进行研究。在这篇综述中，我们概述了最相关的AR变体，并讨论了当前针对AR变体的策略。
