Abstract
BACKGROUND: Isocitrate dehydrogenase (IDH1/2) mutations are common genetic abnormalities in human malignancies, which result in neomorphic enzyme activity that catalyzes 2-hydroxyglutarate (2-HG) production. While IDH mutations are recognized as critical cancer-associated genetic changes, the therapeutic options for IDH-mutated cancers remain limited. METHODS: In the present study, we investigated the reactive oxygen species (ROS) scavenging pathways in patient-derived IDH1-mutated cells. Further, we investigated the protective role of glutathione de novo synthesis for IDH1-mutated cancer cells. Finally, we evaluated triptolide, a diterpenoid epoxide derived from Tripterygium wilfordii, as an experimental therapeutic for IDH1-mutated cells and xenografts. RESULTS: We discovered that the neomorphic activity of IDH1 mutant enzyme triggers metabolic depletion and a substantial elevated burden of ROS scavenging in cancer cells. The nuclear factor erythroid 2-related factor 2 (NRF2)-guided antioxidant pathway plays a key role in maintaining redox homeostasis for IDH1-mutated cells. Triptolide serves as a potent inhibitor of NRF2 through enhancing the NRF2 ubiquitination and subsequently proteasomal degradation. Additionally, triptolide compromises the de novo synthesis of glutathione via suppression of NRF2-guided transcription of SLC7A11, which encodes cystine/glutamate transporter (xCT). Reduced availability of glutathione results in overwhelming oxidative damage in DNA and lipid, which translates into severe cytotoxicity and reduced xenograft expansion of IDH1-mutated cells. CONCLUSION: Overall our findings highlight triptolide as a valuable synthetic lethality approach for IDH1-mutated malignancies by targeting NRF2-guided redox homeostasis.