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A druggable addiction to de novo pyrimidine biosynthesis in diffuse midline glioma. 2022
Sharmistha Pal, and
Jakub P Kaplan, and
Huy Nguyen, and
Sylwia A Stopka, and
Milan R Savani, and
Michael S Regan, and
Quang-De Nguyen, and
Kristen L Jones, and
Lisa A Moreau, and
Jingyu Peng, and
Marina G Dipiazza, and
Andrew J Perciaccante, and
Xiaoting Zhu, and
Bradley R Hunsel, and
Kevin X Liu, and
Sanda Alexandrescu, and
Rachid Drissi, and
Mariella G Filbin, and
Samuel K McBrayer, and
Nathalie Y R Agar, and
Dipanjan Chowdhury, and
Daphne A Haas-Kogan
Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
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.
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