J Natl Cancer Inst. 2019 Oct 1;111(10):1033-1041. doi: 10.1093/jnci/djy230.
Neomorphic IDH1 mutations disrupt the redox balance by promoting reactive oxygen species (ROS) production. However, the mechanism by which IDH1-mutant cells maintain ROS homeostasis remains elusive. It is also not known whether reprogrammed ROS homeostasis establishes targetable vulnerability in IDH1-mutated cancers.
We investigated ROS homeostasis in wild-type (GSC827, GSC923, GSC627, and GSC711) and IDH1-mutated cells (IDH1R132C- and IDH1R132H-transduced U87, U251; MGG152, and TS603 cells). We analyzed the stability and transcriptional activity of NRF2 in IDH1-mutated cells. The oxidative DNA damage was analyzed using NRF2-targeting small interfering RNA. Moreover, we evaluated the effect of the NRF2 inhibitor brusatol in an IDH1-mutated subcutaneous xenograft nude mouse model (control group, n = 5; brusatol-treated group, n = 6). All statistical tests were two-sided.
We showed that IDH1-mutated cells develop a dependency on the NRF2 antioxidative pathway. Genetic or pharmacologic blockade of NRF2 not only disrupted ROS homeostasis (mean [SD] ROS levels increased by 317 [42.1]%, P = .001, in IDH1R132C and by 286. 5 [48.7]%, P = .003, in IDH1R132H cells) but also enhanced oxidative DNA damage and decreased proliferation of IDH1-mutated cells. Brusatol selectively suppressed IDH1-mutated cancer progression in vivo (mean [SD] final tumor volume was 761.6 [391.6] mm3 in the control and 246.2 [215] mm3 in the brusatol-treated group, P = .02).
IDH1 mutation reprograms ROS homeostasis in cancer cells, which leads to dependency on the NRF2 antioxidant pathway for ROS scavenging. NRF2 blockade might be a novel therapeutic approach to treat malignancies with IDH1 mutation.
新形成的 IDH1 突变通过促进活性氧（ROS）的产生来破坏氧化还原平衡。然而，IDH1 突变细胞维持 ROS 动态平衡的机制仍不清楚。也不知道重新编程的 ROS 动态平衡是否在 IDH1 突变的癌症中建立了可靶向的脆弱性。
我们研究了野生型（GSC827、GSC923、GSC627 和 GSC711）和 IDH1 突变细胞（IDH1R132C 和 IDH1R132H 转导的 U87、U251；MGG152 和 TS603 细胞）中的 ROS 动态平衡。我们分析了 IDH1 突变细胞中 NRF2 的稳定性和转录活性。使用靶向 NRF2 的小干扰 RNA 分析氧化 DNA 损伤。此外，我们在 IDH1 突变的皮下异种移植裸鼠模型中评估了 NRF2 抑制剂布瑞佐丁的作用（对照组，n=5；布瑞佐丁治疗组，n=6）。所有统计检验均为双侧检验。
我们表明，IDH1 突变细胞形成了对 NRF2 抗氧化途径的依赖性。NRF2 的遗传或药物阻断不仅破坏了 ROS 动态平衡（IDH1R132C 组 ROS 水平增加 317 [42.1]%，P=0.001，IDH1R132H 组增加 286.5 [48.7]%，P=0.003），而且增强了 IDH1 突变细胞的氧化 DNA 损伤和降低了增殖。布瑞佐丁选择性地抑制了 IDH1 突变的癌症在体内的进展（对照组的最终肿瘤体积为 761.6 [391.6]mm3，布瑞佐丁治疗组为 246.2 [215]mm3，P=0.02）。
IDH1 突变重新编程了癌细胞中的 ROS 动态平衡，导致对 NRF2 抗氧化途径清除 ROS 的依赖性。NRF2 阻断可能是治疗 IDH1 突变恶性肿瘤的一种新的治疗方法。
