Coutinho Isabel, Day Tanya K, Tilley Wayne D, Selth Luke A
Dame Roma Mitchell Cancer Research LaboratoriesSchool of Medicine, The University of Adelaide, Adelaide, South Australia, Australia.
Freemasons Foundation Centre for Men's HealthSchool of Medicine, The University of Adelaide, Adelaide, South Australia, Australia.
Endocr Relat Cancer. 2016 Dec;23(12):T179-T197. doi: 10.1530/ERC-16-0422. Epub 2016 Oct 31.
The androgen receptor (AR) signaling axis drives all stages of prostate cancer, including the lethal, drug-resistant form of the disease termed castration-resistant prostate cancer (CRPC), which arises after failure of androgen deprivation therapy (ADT). Persistent AR activity in spite of ADT and the second-generation AR-targeting agents enzalutamide and abiraterone is achieved in many cases by direct alterations to the AR signaling axis. Herein, we provide a detailed description of how such alterations contribute to the development and progression of CRPC. Aspects of this broad and ever-evolving field specifically addressed in this review include: the etiology and significance of increased AR expression; the frequency and role of gain-of-function mutations in the AR gene; the function of constitutively active, truncated forms of the AR termed AR variants and the clinical relevance of alterations to the activity and expression of AR coregulators. Additionally, we examine the novel therapeutic strategies to inhibit these classes of therapy resistance mechanisms, with an emphasis on emerging agents that act in a manner distinct from the current ligand-centric approaches. Throughout, we discuss how the central role of AR in prostate cancer and the constant evolution of the AR signaling axis during disease progression represent archetypes of two key concepts in oncology, oncogene addiction and therapy-mediated selection pressure.
雄激素受体（AR）信号轴驱动前列腺癌的各个阶段，包括致死性、耐药性疾病形式，即去势抵抗性前列腺癌（CRPC），它在雄激素剥夺治疗（ADT）失败后出现。尽管进行了ADT以及使用了第二代AR靶向药物恩杂鲁胺和阿比特龙，但在许多情况下，通过直接改变AR信号轴仍能实现AR的持续活性。在此，我们详细描述了这些改变如何促进CRPC的发生和发展。本综述特别涉及的这个广泛且不断发展的领域的各个方面包括：AR表达增加的病因和意义；AR基因功能获得性突变的频率和作用；被称为AR变体的组成型活性截短形式的AR的功能以及AR共调节因子活性和表达改变的临床相关性。此外，我们研究了抑制这些类型治疗抵抗机制的新型治疗策略，重点是与当前以配体为中心的方法作用方式不同的新兴药物。在整个过程中，我们讨论了AR在前列腺癌中的核心作用以及疾病进展过程中AR信号轴的不断演变如何代表肿瘤学中两个关键概念——癌基因成瘾和治疗介导的选择压力的原型。
