文章：

前列腺癌中雄激素受体抑制剂耐药的新机制

Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer

原文发布日期：2015-11-13

DOI: 10.1038/nrc4016

类型: Review Article

开放获取: 否

要点：

1. Prostate cancer pathogenesis is dependent on signalling through the steroid nuclear hormone androgen receptor (AR), which is activated after binding of the androgen ligand testosterone or dihydrotestosterone. Ligand-bound AR translocates to the nucleus, where it serves to induce or repress gene expression through binding to chromatin at cis androgen response elements.
2. Medical castration to substantially deplete serum testosterone is the mainstay of therapy for advanced prostate cancer that recurs following surgical removal of the prostate (prostatectomy) or radiotherapy. However, castration therapy is not curative, and patients will eventually progress to lethal castration-resistant prostate cancer (CRPC).
3. Despite a castrate level of testosterone, CRPC almost uniformly remains dependent on AR signalling. Next-generation hormonal therapies for prostate cancer, abiraterone and enzalutamide, are now in widespread clinical use; abiraterone attacks AR signalling through inhibition of extra-gonadal androgen biosynthesis and enzalutamide interferes directly with androgen binding to AR.
4. Resistance mechanisms to these drugs have been identified that result in restoration of AR signalling through gain-of-function AR mutations, upregulation of constitutively active AR splice variants or increased intratumoural androgen biosynthesis. Another resistance mechanism bypasses AR by switching to the related glucocorticoid receptor (GR) to maintain transcriptional regulation of a subset of the same genes.
5. At resistance, a subset of patients are now presenting with low or no AR in their tumours, suggesting that evolution to complex genomic states completely independently of AR could increasingly become a cause for concern.
6. Comprehensive analyses of late-stage CRPC are uncovering multiple genetic lesions in this patient cohort that indicate that it may eventually be possible to stratify patients based on the genomic profile of their cancer. These efforts will aid in clinical trial design and facilitate the use of rationally designed combination strategies to improve patient outcomes.

要点翻译：

1. 前列腺癌的发病机制依赖于类固醇核激素雄激素受体（AR）的信号传导，该受体在与雄激素配体睾酮或二氢睾酮结合后被激活。配体结合的AR易位至细胞核，通过顺式雄激素反应元件与染色质结合，从而诱导或抑制基因表达。
2. 对于前列腺癌切除术后或放疗后复发的晚期前列腺癌，主要通过药物去势大幅降低血清睾酮水平进行治疗。然而，去势疗法并不能治愈疾病，患者最终会进展为致命的去势抵抗性前列腺癌（CRPC）。
3. 尽管睾酮水平处于去势范围，CRPC几乎普遍仍依赖于AR信号传导。新一代前列腺癌激素治疗药物阿比特龙和恩杂鲁胺目前已广泛应用于临床：阿比特龙通过抑制性腺外雄激素生物合成来阻断AR信号传导，恩杂鲁胺则直接干扰雄激素与AR的结合。
4. 针对这些药物的耐药机制已被确认，这些机制通过AR功能获得性突变、组成性活性AR剪接变体的上调或肿瘤内雄激素生物合成的增加，导致AR信号传导的恢复。另一种耐药机制通过转向相关的糖皮质激素受体（GR）来维持同一基因子集的转录调控，从而绕过AR。
5. 在耐药阶段，部分患者的肿瘤组织中AR表达水平较低或完全缺失，这表明完全独立于AR的复杂基因组状态的演变可能日益成为值得关注的原因。
6. 对晚期CRPC的综合分析揭示了该患者队列中存在多种遗传损伤，这表明基于癌症基因组谱对患者进行分层最终可能实现。这些努力将有助于临床试验设计，并促进合理设计的联合策略的应用，以改善患者的治疗效果。

英文摘要：

During the past 10 years, preclinical studies implicating sustained androgen receptor (AR) signalling as the primary driver of castration-resistant prostate cancer (CRPC) have led to the development of novel agents targeting the AR pathway that are now in widespread clinical use. These drugs prolong the survival of patients with late-stage prostate cancer but are not curative. In this Review, we highlight emerging mechanisms of acquired resistance to these contemporary therapies, which fall into the three broad categories of restored AR signalling, AR bypass signalling and complete AR independence. This diverse range of resistance mechanisms presents new challenges for long-term disease control, which may be addressable through early use of combination therapies guided by recent insights from genomic landscape studies of CRPC.

摘要翻译： 

在过去10年中，临床前研究表明，持续的雄激素受体（AR）信号传导是去势抵抗性前列腺癌（CRPC）的主要驱动因素，这促使人们开发出针对AR通路的新型药物，这些药物目前已广泛应用于临床。这些药物延长了晚期前列腺癌患者的生存期，但无法治愈。在本综述中，我们重点介绍了对这些当代疗法获得性耐药的新机制，这些机制可分为三大类：AR信号恢复、AR旁路信号以及完全独立于AR。这种多样化的耐药机制给长期疾病控制带来了新挑战，或许可以通过近期CRPC基因组全景研究所揭示的早期联合治疗来应对。

原文链接：

Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer