A druggable addiction to de novo pyrimidine biosynthesis in diffuse midline glioma

Sharmistha Pal, Jakub P. Kaplan, Huy Nguyen, Sylwia A. Stopka, Milan R. Savani, Michael S. Regan, Quang De Nguyen, Kristen L. Jones, Lisa A. Moreau, Jingyu Peng, Marina G. Dipiazza, Andrew J. Perciaccante, Xiaoting Zhu, Bradley R. Hunsel, Kevin X. Liu, Sanda Alexandrescu, Rachid Drissi, Mariella G. Filbin, Samuel K. McBrayer, Nathalie Y.R. AgarDipanjan Chowdhury, Daphne A. Haas-Kogan

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Diffuse midline glioma (DMG) is a uniformly fatal pediatric cancer driven by oncohistones that do not readily lend themselves to drug development. To identify druggable targets for DMG, we conducted a genome-wide CRISPR screen that reveals a DMG selective dependency on the de novo pathway for pyrimidine biosynthesis. This metabolic vulnerability reflects an elevated rate of uridine/uracil degradation that depletes DMG cells of substrates for the alternate salvage pyrimidine biosynthesis pathway. A clinical stage inhibitor of DHODH (rate-limiting enzyme in the de novo pathway) diminishes uridine-5′-phosphate (UMP) pools, generates DNA damage, and induces apoptosis through suppression of replication forks—an “on-target” effect, as shown by uridine rescue. Matrix-assisted laser desorption/ionization (MALDI) mass spectroscopy imaging demonstrates that this DHODH inhibitor (BAY2402234) accumulates in the brain at therapeutically relevant concentrations, suppresses de novo pyrimidine biosynthesis in vivo, and prolongs survival of mice bearing intracranial DMG xenografts, highlighting BAY2402234 as a promising therapy against DMGs.

Original languageEnglish (US)
Pages (from-to)957-972.e10
JournalCancer Cell
Volume40
Issue number9
DOIs
StatePublished - Sep 12 2022

Keywords

  • ATR
  • BAY2402234
  • de novo pyrimidine synthesis
  • DHODH
  • diffuse intrinsic pontine glioma
  • diffuse midline glioma
  • DPYD
  • elimusertib
  • pyrimidine degradation
  • replication stress

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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