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IDH-mutant inhibitors enhance the sensitivity of IDH1-mutant gliomas to cysteine-methionine deprivation and ferroptosis

Canoll, P.; Mela, A.; Brand, A.; Mahajan, A.; Dovas, A.; Humala, N.; Kanangat, S.; Kleinstein, A.; Leskinen, S.; Nguyen, T.; Gao, Q.; Upadhyayula, P.; Guo, J.; Gill, B.; Siegelin, M.; Sims, P.; Stockwell, B.; Bruce, J.

2026-02-02 cancer biology
10.64898/2026.01.30.702627 bioRxiv
Show abstract

Cysteine is essential for synthesizing glutathione, the brains main antioxidant, and cysteine deprivation can trigger ferroptosis. Here, using a new mouse model of IDH1-mutant glioma that recapitulates the characteristics of human IDH1-mutant low-grade gliomas, we demonstrate that IDH1-mutant glioma cells are significantly more vulnerable to cysteine deprivation alone or in combination with the ferroptosis inducer RSL3, compared to IDH1-wildtype glioma cells. In addition, treatments with the IDH-mutant inhibitors vorasidenib and ivosidenib further sensitize the cells to ferroptosis. Metabolomics analysis reveals that IDH1-mutant cells have altered cysteine and methionine metabolism with deficiency in transsulfuration, which is further exacerbated by cysteine-methionine deprivation and IDH-mutant inhibitors. Furthermore, dietary cysteine-methionine deprivation alone or in combination with convection-enhanced delivery of RSL3 or ivosidenib in vivo significantly prolongs survival of IDH1-mutant tumor-bearing mice. Our findings suggest that targeting cysteine and methionine metabolism in combination with IDH-mutant inhibition provides promising therapeutic strategies for IDH1-mutant gliomas.

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