Blockade of Glutathione Metabolism in IDH1-Mutated Glioma

Abstract Mutations in genes encoding isocitrate dehydrogenases (IDH) 1 and 2 are common cancer-related genetic abnormalities. Malignancies with mutated IDHs exhibit similar pathogenesis, metabolic pattern, and resistance signature. However, an effective therapy against IDH1-mutated solid tumor remains unavailable. In this study, we showed that acquisition of IDH1 mutation results in the disruption of NADP+/NADPH balance and an increased demand for glutathione (GSH) metabolism. Moreover, the nuclear factor erythroid 2–related factor 2 (Nrf2) plays a key protective role in IDH1-mutated cells by prompting GSH synthesis and reactive oxygen species scavenging. Pharmacologic inhibition of the Nrf2/GSH pathway via brusatol administration exhibited a potent tumor suppressive effect on IDH1-mutated cancer in vitro and in vivo. Our findings highlight a possible therapeutic strategy that could be valuable for IDH1-mutated cancer treatment.