| Literature DB >> 35985342 |
Sharmistha Pal1, Jakub P Kaplan1, Huy Nguyen1, Sylwia A Stopka2, Milan R Savani3, Michael S Regan4, Quang-De Nguyen5, Kristen L Jones5, Lisa A Moreau6, Jingyu Peng7, Marina G Dipiazza4, Andrew J Perciaccante4, Xiaoting Zhu8, Bradley R Hunsel1, Kevin X Liu9, Sanda Alexandrescu10, Rachid Drissi8, Mariella G Filbin11, Samuel K McBrayer12, Nathalie Y R Agar13, Dipanjan Chowdhury14, Daphne A Haas-Kogan15.
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.Entities:
Keywords: ATR; BAY2402234; DHODH; DPYD; de novo pyrimidine synthesis; diffuse intrinsic pontine glioma; diffuse midline glioma; elimusertib; pyrimidine degradation; replication stress
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Year: 2022 PMID： 35985342 PMCID： PMC9575661 DOI： 10.1016/j.ccell.2022.07.012
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 38.585