Author:
Shi Diana D.,Savani Milan R.,Levitt Michael M.,Wang Adam C.,Endress Jennifer E.,Bird Cylaina E.,Buehler Joseph,Stopka Sylwia A.,Regan Michael S.,Lin Yu-Fen,Gao Wenhua,Khanal Januka,Xu Min,Huang Bofu,Jennings Rebecca B.,Bonal Dennis M.,Martin-Sandoval Misty S.,Dang Tammie,Gattie Lauren C.,Lee Sungwoo,Asara John M.,Kornblum Harley I.,Mak Tak W.,Looper Ryan E.,Nguyen Quang-De,Signoretti Sabina,Gradl Stefan,Sutter Andreas,Jeffers Michael,Janzer Andreas,Lehrman Mark A.,Zacharias Lauren G.,Mathews Thomas P.,Richardson Timothy E.,Cahill Daniel P.,DeBerardinis Ralph J.,Ligon Keith L.,Ly Peter,Agar Nathalie Y. R.,Abdullah Kalil G.,Harris Isaac S.,Kaelin William G.,McBrayer Samuel K.
Abstract
SUMMARYMutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they appear 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 vulnerability selectively applies to de novo pyrimidine, but not purine, synthesis because glioma cells engage disparate programs to produce these nucleotide species and because IDH oncogenes increase DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.
Publisher
Cold Spring Harbor Laboratory