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 Agar, Dipanjan Chowdhury, Daphne A Haas-Kogan
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...
September 12, 2022: Cancer Cell