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

Diana D. Shi, Milan R. Savani, Michael M. Levitt, Adam C. Wang, Jennifer E. Endress, Cylaina E. Bird, Joseph Buehler, Sylwia A. Stopka, Michael S. Regan, Yu Fen Lin, Vinesh Thidil Puliyappadamba, Wenhua Gao, Januka Khanal, Laura Evans, Joyce H. Lee, Lei Guo, Yi Xiao, Min Xu, Bofu Huang, Rebecca B. JenningsDennis M. Bonal, Misty S. Martin-Sandoval, Tammie Dang, Lauren C. Gattie, Amy B. Cameron, Sungwoo Lee, John M. Asara, Harley I. Kornblum, Tak W. Mak, Ryan E. Looper, Quang De Nguyen, Sabina Signoretti, Stefan Gradl, Andreas Sutter, Michael Jeffers, Andreas Janzer, Mark A. Lehrman, Lauren G. Zacharias, Thomas P. Mathews, Julie Aurore Losman, Timothy E. Richardson, Daniel P. Cahill, Ralph J. DeBerardinis, Keith L. Ligon, Lin Xu, Peter Ly, Nathalie Y.R. Agar, Kalil Abdullah, Isaac S. Harris, William G. Kaelin, Samuel K. McBrayer

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)939-956.e16
JournalCancer Cell
Volume40
Issue number9
DOIs
StatePublished - Sep 12 2022

Keywords

  • cancer metabolism
  • DHODH
  • genetically engineered mouse model
  • glioma
  • IDH
  • isocitrate dehydrogenase
  • pyrimidine nucleotides

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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