Yang Lu, Zhang Youyou, Shan Weiwei, Hu Zhongyi, Yuan Jiao, Pi Jingjiang, Wang Yueying, Fan Lingling, Tang Zhaoqing, Li Chunsheng, Hu Xiaowen, Tanyi Janos L, Fan Yi, Huang Qihong, Montone Kathleen, Dang Chi V, Zhang Lin
Center for Research on Reproduction and Women's Health, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Obstetrics and Gynecology, West China Medical School, Sichuan University, Chengdu 610041, China.
Sci Transl Med. 2017 Jul 26;9(400). doi: 10.1126/scitranslmed.aal1645.
Strategies to enhance response to poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi) in primary and acquired homologous recombination (HR)-proficient tumors would be a major advance in cancer care. We used a drug synergy screen that combined a PARPi, olaparib, with 20 well-characterized epigenetic drugs and identified bromodomain and extraterminal domain inhibitors (BETis; JQ1, I-BET762, and OTX015) as drugs that acted synergistically with olaparib in HR-proficient cancer cells. Functional assays demonstrated that repressed BET activity reduces HR and thus enhances PARPi-induced DNA damage in cancer cells. We also found that inhibition or depletion of BET proteins impairs transcription of and , two genes essential for HR. Moreover, BETi treatment sensitized tumors to PARP inhibition in preclinical animal models of HR-proficient breast and ovarian cancers. Finally, we showed that the gene was focally amplified across 20 types of common cancers. Combination with BETi could greatly expand the utility of PARP inhibition to patients with HR-proficient cancer.
增强原发性和获得性同源重组（HR） proficient肿瘤对聚（腺苷二磷酸核糖）聚合酶抑制剂（PARPi）反应的策略将是癌症治疗的一项重大进展。我们使用了一种药物协同筛选方法，将PARPi奥拉帕利与20种特征明确的表观遗传药物相结合，确定了溴结构域和额外末端结构域抑制剂（BETis；JQ1、I-BET762和OTX015）为在HR proficient癌细胞中与奥拉帕利协同作用的药物。功能分析表明，抑制BET活性会降低HR，从而增强PARPi诱导的癌细胞DNA损伤。我们还发现，抑制或耗尽BET蛋白会损害HR必需的两个基因 和 的转录。此外，在HR proficient乳腺癌和卵巢癌的临床前动物模型中，BETi治疗使肿瘤对PARP抑制敏感。最后，我们表明 基因在20种常见癌症中发生局部扩增。与BETi联合使用可大大扩大PARP抑制对HR proficient癌症患者的应用范围。
