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

Authors
  • Pal, Sharmistha1
  • Kaplan, Jakub P1
  • Nguyen, Huy1
  • Stopka, Sylwia A2
  • Savani, Milan R3
  • Regan, Michael S4
  • Nguyen, Quang-De5
  • Jones, Kristen L5
  • Moreau, Lisa A6
  • Peng, Jingyu7
  • Dipiazza, Marina G4
  • Perciaccante, Andrew J4
  • Zhu, Xiaoting8
  • Hunsel, Bradley R1
  • Liu, Kevin X9
  • Alexandrescu, Sanda10
  • Drissi, Rachid8
  • Filbin, Mariella G11
  • McBrayer, Samuel K12
  • Agar, Nathalie Y R13
  • And 2 more
  • 1 Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 2 Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • 3 Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 4 Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • 5 Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02210, USA.
  • 6 Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 7 Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 8 Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
  • 9 Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Radiation Oncology, Brigham and Women's Hospital, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • 10 Department of Pathology, Harvard Medical School Boston, Boston Children's Hospital, 300 Longwood Avenue, Bader 104, Boston, MA 02115, USA.
  • 11 Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02115, USA.
  • 12 Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 13 Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 14 Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • 15 Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Radiation Oncology, Brigham and Women's Hospital, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA. Electronic address: [email protected].
Type
Published Article
Journal
Cancer cell
Publication Date
Sep 12, 2022
Volume
40
Issue
9
Identifiers
DOI: 10.1016/j.ccell.2022.07.012
PMID: 35985342
Source
Medline
Keywords
Language
English
License
Unknown

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. Copyright © 2022 Elsevier Inc. All rights reserved.

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