Wang Yuxiang, Wild Aaron T, Turcan Sevin, Wu Wei H, Sigel Carlie, Klimstra David S, Ma Xiaoxiao, Gong Yongxing, Holland Eric C, Huse Jason T, Chan Timothy A
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Sci Adv. 2020 Apr 22;6(17):eaaz3221. doi: 10.1126/sciadv.aaz3221. eCollection 2020 Apr.
Mutations in isocitrate dehydrogenase (IDH) genes occur in multiple cancer types, lead to global changes in the epigenome, and drive tumorigenesis. Yet, effective strategies targeting solid tumors harboring IDH mutations remain elusive. Here, we demonstrate that IDH-mutant gliomas and cholangiocarcinomas display elevated DNA damage. Using multiple in vitro and preclinical animal models of glioma and cholangiocarcinoma, we developed treatment strategies that use a synthetic lethality approach targeting the reduced DNA damage repair conferred by mutant IDH using poly(adenosine 5'-diphosphate) ribose polymerase inhibitors (PARPis). The therapeutic effects are markedly enhanced by cotreatment with concurrent, localized radiation therapy. PARPi-buttressed multimodality therapies may represent a readily applicable approach that is selective for IDH-mutant tumor cells and has potential to improve outcomes in multiple cancers.
异柠檬酸脱氢酶（IDH）基因突变存在于多种癌症类型中，会导致表观基因组的整体变化，并驱动肿瘤发生。然而，针对携带IDH突变的实体瘤的有效策略仍然难以捉摸。在这里，我们证明IDH突变型神经胶质瘤和胆管癌表现出DNA损伤增加。利用神经胶质瘤和胆管癌的多种体外和临床前动物模型，我们开发了治疗策略，该策略采用合成致死方法，使用聚（腺苷5'-二磷酸）核糖聚合酶抑制剂（PARPis）来靶向由突变IDH导致的DNA损伤修复减少。同时进行局部放射治疗可显著增强治疗效果。PARPi支持的多模态疗法可能是一种易于应用的方法，对IDH突变肿瘤细胞具有选择性，并且有可能改善多种癌症的治疗结果。
