Asim Mohammad, Tarish Firas, Zecchini Heather I, Sanjiv Kumar, Gelali Eleni, Massie Charles E, Baridi Ajoeb, Warren Anne Y, Zhao Wanfeng, Ogris Christoph, McDuffus Leigh-Anne, Mascalchi Patrice, Shaw Greg, Dev Harveer, Wadhwa Karan, Wijnhoven Paul, Forment Josep V, Lyons Scott R, Lynch Andy G, O'Neill Cormac, Zecchini Vincent R, Rennie Paul S, Baniahmad Aria, Tavaré Simon, Mills Ian G, Galanty Yaron, Crosetto Nicola, Schultz Niklas, Neal David, Helleday Thomas
Cancer Research UK Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, CB2 0RE, UK.
Department of Clinical and Experimental Medicine, University of Surrey, Guildford, GU2 7WG, UK.
Nat Commun. 2017 Aug 29;8(1):374. doi: 10.1038/s41467-017-00393-y.
Emerging data demonstrate homologous recombination (HR) defects in castration-resistant prostate cancers, rendering these tumours sensitive to PARP inhibition. Here we demonstrate a direct requirement for the androgen receptor (AR) to maintain HR gene expression and HR activity in prostate cancer. We show that PARP-mediated repair pathways are upregulated in prostate cancer following androgen-deprivation therapy (ADT). Furthermore, upregulation of PARP activity is essential for the survival of prostate cancer cells and we demonstrate a synthetic lethality between ADT and PARP inhibition in vivo. Our data suggest that ADT can functionally impair HR prior to the development of castration resistance and that, this potentially could be exploited therapeutically using PARP inhibitors in combination with androgen-deprivation therapy upfront in advanced or high-risk prostate cancer.Tumours with homologous recombination (HR) defects become sensitive to PARPi. Here, the authors show that androgen receptor (AR) regulates HR and AR inhibition activates the PARP pathway in vivo, thus inhibition of both AR and PARP is required for effective treatment of high risk prostate cancer.
新出现的数据表明，去势抵抗性前列腺癌存在同源重组（HR）缺陷，使得这些肿瘤对PARP抑制敏感。在此，我们证明雄激素受体（AR）对于维持前列腺癌中HR基因表达和HR活性具有直接需求。我们表明，在雄激素剥夺疗法（ADT）后，PARP介导的修复途径在前列腺癌中上调。此外，PARP活性的上调对于前列腺癌细胞的存活至关重要，并且我们在体内证明了ADT与PARP抑制之间的合成致死性。我们的数据表明，ADT在去势抵抗发生之前可在功能上损害HR，并且这在治疗上可能可以通过在晚期或高危前列腺癌中 upfront 将PARP抑制剂与雄激素剥夺疗法联合使用来加以利用。具有同源重组（HR）缺陷的肿瘤对PARPi敏感。在此，作者表明雄激素受体（AR）调节HR，并且AR抑制在体内激活PARP途径，因此抑制AR和PARP对于有效治疗高危前列腺癌是必需的。
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