Targeting IDH1-Mutated Malignancies with NRF2 Blockade

Abstract

Background 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. Methods 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. Results 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). Conclusions 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.

Targeting NRF2-Governed Glutathione Synthesis for SDHB-Mutated Pheochromocytoma and Paraganglioma

“…In the present study, the NRF2-derived de novo glutathione synthesis pathway was targeted as a therapeutic approach for PCPGs with SDHB deficiency. Brusatol has been repeatedly shown to be a potent inhibitor for NRF2 and antioxidant pathways [24,[36][37][38][39]. Several studies have indicated that brusatol alone exhibits mild cytotoxic effects and is frequently evaluated as a sensitization approach to support other cytotoxic therapies such as radiation therapy and cisplatin [24,40,41].…”

Brusatol suppresses STAT3-driven metastasis by downregulating epithelial-mesenchymal transition in hepatocellular carcinoma

“…The same group also demonstrated that isocitrate dehydrogenase (IDH) 1-mutated glioma cells are dependent on Nrf-2 signaling cascade. The inhibition of Nrf-2 by BT increased oxidative damage to DNA with reduction in proliferation of IDH1-mutated cells [34] . They also reported that Nrf-2 can promote glutathione synthesis and thereby display protective function towards IDH1-mutated cells [35] .…”

“…The abrogation of Nrf2/GSH pathway by BT resulted in potent anticancer effect on IDH1-mutated preclinical cancer models [35] . In addition, the effect of BT on glutathione metabolism, ROS production, and chemoresistance in breast cancer has been reported in the literature [33] , [34] , [35] , [36] , [37] . Besides, Yang et al described the effect of BT on various types of cancer cells, Nrf-2-guided gene transcription, and glutathione de novo synthesis [37] .…”

Mutant IDH1 Depletion Downregulates Integrins and Impairs Chondrosarcoma Growth

“…While the inhibitors, AG-120 and AG-221 elicit partial responses or complete remission in AML patients, preclinical responses in solid tumors are less consistent and less robust. To enhance the antitumor effect of IDH mut inhibitors, particularly in low-grade gliomas, a few preclinical studies investigated synthetic lethal interactions of these inhibitors, with other reagents such as NAMPT inhibitors [48], Bcl-2 inhibitors [49], NRF2 inhibitors [50], PARP inhibitors [51], and tyrosine kinase inhibitors [52]. The combinatorial regimens have proven to be more effective.…”