TMET-43. IDH1(R132H) inhibitors enhance the sensitivity of IDH1-mutant glioma to cysteine deprivation and ferroptosis

Abstract Cysteine is a key molecule in the production of glutathione, the main antioxidant in the brain, and cysteine deprivation has been shown to sensitize cells to ferroptosis. In this study, using a newly developed mouse model of IDH1(R132H) glioma, we show that IDH1-mutant gliomas are dependent on cysteine metabolism, and treatment with IDH(R132H) inhibitors enhances their sensitivity to cysteine deprivation. In this model, which harbors the IDH1(R132H) mutation in heterozygous condition in combination with p53 deletion and PDGFA expression, mice with IDH1-mutant tumors survive longer compared to their IDH1-wildtype counterparts, while histological analysis reveals characteristics of low-grade diffuse gliomas. IDH1-mutant glioma cells are sensitive to mitochondrial stress and have an altered metabolic profile which indicates both a dependence on cysteine metabolism and a sensitivity to ferroptosis-inducing treatments. In vitro treatments with cysteine deprivation alone or in combination with RSL3, a GPX-4 inhibitor, significantly impair IDH1-mutant glioma cell viability and this effect is enhanced by IDH1(R132H) inhibitors. Finally, convection-enhanced delivery of RSL3 or the IDH1(R132H) inhibitor Ivosidenib, alone or in combination with dietary cysteine deprivation in vivo, significantly prolongs survival of IDH1-mutant tumor bearing mice. Our findings suggest that targeting cysteine metabolism and ferroptosis in addition to IDH1(R132H) inhibition provide promising therapeutic strategies for IDH1-mutant gliomas.