Isocitrate Dehydrogenase 1 Primes Group-3 Medulloblastomas For Cuproptosis

MYC-driven Group-3 medulloblastomas (MB) are malignant pediatric brain cancers without cures. To define actionable metabolic dependencies, we identified upregulationof dihydrolipoyl transacetylase (DLAT), the E2-subunit of pyruvate dehydrogenasecomplex (PDC) in a subset of Group-3 MB with poor prognosis. DLAT was induced by c-MYC and targeting DLAT lowered TCA-cycle metabolism and glutathione synthesis in Group-3 MB cells. We also noted upregulation of isocitrate dehydrogenase 1 (IDH1) in Group-3 MB. Remarkably, genetic and pharmacologic suppression of IDH1 epigenetically reduced c-MYC and downstream DLAT levels. DLAT is a central regulator of cuproptosis, a copper-dependent cell death mechanism induced by the copper ionophore elesclomol. DLAT expression in Group-3 MB cells correlated with increased sensitivity to cuproptosis. Elesclomol was CNS-penetrant and suppressed tumor growth in vivo in Group-3 MB animal models. Our data uncover an IDH1/c-MYC dependent vulnerability that regulates DLAT levels and can be targeted to kill Group-3MB by cuproptosis.