Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma

Cancer Cell. 2022 Dec 12;40(12):1488-1502.e7. doi: 10.1016/j.ccell.2022.10.009. Epub 2022 Nov 10.


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.

Keywords: DHODH; brain tumor initiating cells; c-Myc; medulloblastoma; metabolic reprogramming; pyrimidine metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cerebellar Neoplasms* / drug therapy
  • Cerebellar Neoplasms* / genetics
  • Cerebellar Neoplasms* / metabolism
  • Child
  • Dihydroorotate Dehydrogenase
  • Humans
  • Medulloblastoma* / drug therapy
  • Medulloblastoma* / genetics
  • Medulloblastoma* / metabolism
  • Neoplasm Recurrence, Local
  • Pyrimidines / therapeutic use


  • Dihydroorotate Dehydrogenase
  • Pyrimidines

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