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. To understand the changes in gene expression upon induction of cuproptosis in Gr3 medulloblastoma, D283 medulloblastoma cells were treated with copper ionophore Elesclomol. RNAseq was performed in D283 cells with or without elesclomol (12.5 nM) treatment for 48 hrs. To understand the role of overexpression of c-MYC protein in Gr3 medulloblastoma, c-MYC was overexpressed in human cerebellar neuronal stem cells [Hanaford et al, 2017]. RNASeq was performed in cell with or without c-MYC overexpression. To understand the role of IDH1 protein expression in Gr3 medulloblastoma, D283 medulloblastoma cells were transfected with siRNA targeting IDH1. To understand the role of IDH1 protein expression in Gr3 medulloblastoma, D283 medulloblastoma cells were treated with IDH1 inhibitor and Cut and Run was performed.