Minnesota Supercomputing Institute, University of Minnesota, 117 Pleasant Street Southeast, Minneapolis, Minnesota 55455, USA.
Masonic Cancer Center, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street Southeast, Minneapolis, Minnesota 55455, USA.
Nat Commun. 2016 Nov 29;7:13668. doi: 10.1038/ncomms13668.
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.
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法。然而，即使患者接受了强效的第二代 AR 靶向治疗药物阿比特龙和恩杂鲁胺，持续的 AR 信号也会破坏治疗效果，并促进致命的去势抵抗性前列腺癌（CRPC）的进展。在这里，我们将不同的 AR 基因组结构重排（AR-GSRs）定义为一类在三分之一的 CRPC 期肿瘤中发生的分子改变。AR-GSRs 发生在拷贝中性和扩增的 AR 背景下，在断点位置、重排类型以及患者内和患者间肿瘤中的亚克隆富集方面表现出异质性。尽管存在这种异质性，但在 AR-GSR 高亚克隆富集的肿瘤中，一个常见的结果是各种缺乏配体结合域且具有配体非依赖性转录活性的 AR 变体的异常表达。总之，这些发现揭示了 AR-GSRs 是 CRPC 中持续的 AR 信号的重要驱动因素。
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