De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma

Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they seem to be less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1-mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH-mutant gliomas. Mechanistically, this reflects an obligate dependence of glioma cells on the de novo pyrimidine synthesis pathway and mutant IDH’s ability to sensitize to DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation. • IDH-mutant gliomas are hyperdependent on de novo pyrimidine nucleotide synthesis • IDH mutations and 2HG levels predict sensitivity to the DHODH inhibitor BAY 2402234 • Allografts from a GEM model of mutant IDH-driven astrocytoma respond to BAY 2402234 • IDH mutations enhance DNA damage caused by nucleotide pool imbalance Shi et al. show that IDH-mutant gliomas are hyperdependent on de novo pyrimidine nucleotide synthesis. Using a newly developed, genetically engineered mouse model of IDH mutant glioma and patient-derived models, they show that blocking pyrimidine synthesis with the DHODH inhibitor BAY 2402234 is effective against these tumors.