Development and exploitation of a novel mutant androgen receptor modelling strategy to identify new targets for advanced prostate cancer therapy.
Development and exploitation of a novel mutant androgen receptor modelling strategy to identify new targets for advanced prostate cancer therapy.
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DOI：
10.18632/oncotarget.4347
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发表时间：
2015-09-22
期刊：
影响因子：
--
通讯作者：
Gaughan L
中科院分区：
文献类型：
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作者：
O'Neill D;Jones D;Wade M;Grey J;Nakjang S;Guo W;Cork D;Davies BR;Wedge SR;Robson CN;Gaughan L
去势抵抗性前列腺癌（CRPC）中雄激素受体（AR）信号传导的持续性突出了开发更有效的AR靶向治疗的未满足的临床需求。治疗抗性的一个关键机制是通过选择将抗雄激素转化为激动剂的AR突变，使CRPC中的雄激素信号传导得以保留。为了提高我们对晚期疾病中这些受体的理解，我们开发了一种生理学相关模型来分析CRPC中AR突变体的整体功能。使用比卡鲁胺激活的ARW 741 L/C突变作为概念证明，我们证明了该突变体在比卡鲁胺存在下赋予雄激素样信号传导程序和生长促进表型。ARW 741 L的转录组学分析突出了突变受体显著上调的关键基因，包括TIPARP，RASD 1和SGK 1。重要的是，发现SGK 1表达在KUCaP异种移植模型和CRPC患者活检样品中高度表达，这两种模型都表达比卡鲁胺激活的受体突变体。使用SGK 1抑制剂，ARW 741 L转录和生长促进活性降低，表明在我们的模型中利用受体亚型之间的功能差异可能为CRPC患者提供新的有效疗法。
The persistence of androgen receptor (AR) signalling in castrate-resistant prostate cancer (CRPC) highlights the unmet clinical need for the development of more effective AR targeting therapies. A key mechanism of therapy-resistance is by selection of AR mutations that convert anti-androgens to agonists enabling the retention of androgenic signalling in CRPC. To improve our understanding of these receptors in advanced disease we developed a physiologically-relevant model to analyse the global functionality of AR mutants in CRPC. Using the bicalutamide-activated ARW741L/C mutation as proof of concept, we demonstrate that this mutant confers an androgenic-like signalling programme and growth promoting phenotype in the presence of bicalutamide. Transcriptomic profiling of ARW741L highlighted key genes markedly up-regulated by the mutant receptor, including TIPARP, RASD1 and SGK1. Importantly, SGK1 expression was found to be highly expressed in the KUCaP xenograft model and a CRPC patient biopsy sample both of which express the bicalutamide-activated receptor mutant. Using an SGK1 inhibitor, ARW741L transcriptional and growth promoting activity was reduced indicating that exploiting functional distinctions between receptor isoforms in our model may provide new and effective therapies for CRPC patients.