1. Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma
- Author
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William D. Gwynne, Yujin Suk, Stefan Custers, Nicholas Mikolajewicz, Jeremy K. Chan, Zsolt Zador, Shawn C. Chafe, Kui Zhai, Laura Escudero, Cunjie Zhang, Olga Zaslaver, Chirayu Chokshi, Muhammad Vaseem Shaikh, David Bakhshinyan, Ian Burns, Iqra Chaudhry, Omri Nachmani, Daniel Mobilio, William T. Maich, Patricia Mero, Kevin R. Brown, Andrew T. Quaile, Chitra Venugopal, Jason Moffat, J. Rafael Montenegro-Burke, and Sheila K. Singh
- Subjects
Cancer Research ,Pyrimidines ,Oncology ,Cell Line, Tumor ,Dihydroorotate Dehydrogenase ,Humans ,Neoplasm Recurrence, Local ,Child ,Cerebellar Neoplasms ,Medulloblastoma - Abstract
MYC-driven medulloblastoma (MB) is an aggressive pediatric brain tumor characterized by therapy resistance and disease recurrence. Here, we integrated data from unbiased genetic screening and metabolomic profiling to identify multiple cancer-selective metabolic vulnerabilities in MYC-driven MB tumor cells, which are amenable to therapeutic targeting. Among these targets, dihydroorotate dehydrogenase (DHODH), an enzyme that catalyzes de novo pyrimidine biosynthesis, emerged as a favorable candidate for therapeutic targeting. Mechanistically, DHODH inhibition acts on target, leading to uridine metabolite scarcity and hyperlipidemia, accompanied by reduced protein O-GlcNAcylation and c-Myc degradation. Pyrimidine starvation evokes a metabolic stress response that leads to cell-cycle arrest and apoptosis. We further show that an orally available small-molecule DHODH inhibitor demonstrates potent mono-therapeutic efficacy against patient-derived MB xenografts in vivo. The reprogramming of pyrimidine metabolism in MYC-driven medulloblastoma represents an unappreciated therapeutic strategy and a potential new class of treatments with stronger cancer selectivity and fewer neurotoxic sequelae.
- Published
- 2022