Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer.
Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer.
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DOI：
10.1038/ncomms13668
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发表时间：
2016-11-29
影响因子：
16.6
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晚期前列腺癌的分子靶向治疗包括抑制雄激素受体 (AR) 配体依赖性转录活性的去势方式。然而，持续的 AR 信号传导会破坏治疗效果，并促进进展为致命的去势抵抗性前列腺癌 (CRPC)，即使患者接受有效的第二代 AR 靶向疗法阿比特龙和恩杂鲁胺治疗也是如此。在这里，我们将多种 AR 基因组结构重排 (AR-GSR) 定义为在三分之一的 CRPC 阶段肿瘤中发生的一类分子改变。 AR-GSR 发生在复制中性和扩增 AR 的背景下，并在患者体内和患者之间的肿瘤中的断点位置、重排类别和亚克隆富集方面表现出异质性。尽管存在这种异质性，但 AR-GSR 亚克隆高度富集的肿瘤中的一个常见结果是缺乏配体结合结构域并具有配体独立转录活性的多种 AR 变体物种的异常表达。总的来说，这些发现表明 AR-GSR 是 CRPC 中持续 AR 信号传导的重要驱动因素。 去势抵抗性前列腺癌经常出现持续的雄激素受体信号传导。在这里，作者发现雄激素受体会发生基因重排，从而产生具有配体独立活性的变体。
Molecularly targeted therapies for advanced prostate cancer include castration modalities that suppress ligand-dependent transcriptional activity of the androgen receptor (AR). However, persistent AR signalling undermines therapeutic efficacy and promotes progression to lethal castration-resistant prostate cancer (CRPC), even when patients are treated with potent second-generation AR-targeted therapies abiraterone and enzalutamide. Here we define diverse AR genomic structural rearrangements (AR-GSRs) as a class of molecular alterations occurring in one third of CRPC-stage tumours. AR-GSRs occur in the context of copy-neutral and amplified AR and display heterogeneity in breakpoint location, rearrangement class and sub-clonal enrichment in tumours within and between patients. Despite this heterogeneity, one common outcome in tumours with high sub-clonal enrichment of AR-GSRs is outlier expression of diverse AR variant species lacking the ligand-binding domain and possessing ligand-independent transcriptional activity. Collectively, these findings reveal AR-GSRs as important drivers of persistent AR signalling in CRPC. Castration-resistant prostate cancer frequently presents with persistent androgen receptor signalling. Here, the authors find that the androgen receptor is subject to genetic rearrangements, resulting in variants with ligand-independent activity.