Department of Pathology, Duke University, Durham, NC, USA; The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC, USA.
Department of Pathology, Duke University, Durham, NC, USA; The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC, USA.
Cancer Cell. 2018 Aug 13;34(2):186-195. doi: 10.1016/j.ccell.2018.04.011. Epub 2018 May 24.
Hotspot mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) occur in a variety of myeloid malignancies and solid tumors. Mutant IDH proteins acquire a neomorphic enzyme activity to produce the putative oncometabolite D-2-hydroxyglutarate, which is thought to block cellular differentiation by competitively inhibiting α-ketoglutarate-dependent dioxygenases involved in histone and DNA demethylation. Small-molecule inhibitors of mutant IDH1 and IDH2 have been developed and are progressing through pre-clinical and clinical development. In this review, we provide an overview of mutant IDH-targeted therapy and discuss a number of important recent pre-clinical studies using models of IDH-mutant solid tumors.
热点突变发生在异柠檬酸脱氢酶 1（IDH1）和异柠檬酸脱氢酶 2（IDH2）在各种髓系恶性肿瘤和实体瘤中。突变 IDH 蛋白获得新的酶活性，产生假定的致癌代谢物 D-2-羟基戊二酸，据认为通过竞争性抑制参与组蛋白和 DNA 去甲基化的α-酮戊二酸依赖性加双氧酶，阻止细胞分化。已经开发出突变 IDH1 和 IDH2 的小分子抑制剂，并正在进行临床前和临床开发。在这篇综述中，我们概述了突变 IDH 靶向治疗，并讨论了一些使用 IDH 突变型实体瘤模型的重要的最新临床前研究。
