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De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma. 2022
Diana D Shi, and
Milan R Savani, and
Michael M Levitt, and
Adam C Wang, and
Jennifer E Endress, and
Cylaina E Bird, and
Joseph Buehler, and
Sylwia A Stopka, and
Michael S Regan, and
Yu-Fen Lin, and
Vinesh T Puliyappadamba, and
Wenhua Gao, and
Januka Khanal, and
Laura Evans, and
Joyce H Lee, and
Lei Guo, and
Yi Xiao, and
Min Xu, and
Bofu Huang, and
Rebecca B Jennings, and
Dennis M Bonal, and
Misty S Martin-Sandoval, and
Tammie Dang, and
Lauren C Gattie, and
Amy B Cameron, and
Sungwoo Lee, and
John M Asara, and
Harley I Kornblum, and
Tak W Mak, and
Ryan E Looper, and
Quang-De Nguyen, and
Sabina Signoretti, and
Stefan Gradl, and
Andreas Sutter, and
Michael Jeffers, and
Andreas Janzer, and
Mark A Lehrman, and
Lauren G Zacharias, and
Thomas P Mathews, and
Julie-Aurore Losman, and
Timothy E Richardson, and
Daniel P Cahill, and
Ralph J DeBerardinis, and
Keith L Ligon, and
Lin Xu, and
Peter Ly, and
Nathalie Y R Agar, and
Kalil G Abdullah, and
Isaac S Harris, and
William G Kaelin, and
Samuel K McBrayer
Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA 02215, USA; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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.
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