Isocitrate dehydrogenase 1 primes group-3 medulloblastomas for cuproptosis
Menée à l'aide de lignées cellulaires, d'échantillons tumoraux et de modèles murins de médulloblastome de groupe 3, cette étude met en évidence un mécanisme par lequel l'isocitrate déshydrogénase 1, via l'augmentation du niveau d'expression de la dihydrolipoyl transacylase, sensibilise les cellules cancéreuses à la cuproptose induite par l'élesclomol
MYC-driven group-3 medulloblastomas (MBs) are malignant pediatric brain cancers without cures. To define actionable metabolic dependencies, we identify upregulation of dihydrolipoyl transacetylase (DLAT), the E2-subunit of pyruvate dehydrogenase complex (PDC) in a subset of group-3 MB with poor prognosis. DLAT is induced by c-MYC and targeting DLAT lowers TCA cycle metabolism and glutathione synthesis. We also note upregulation of isocitrate dehydrogenase 1 (IDH1) gene expression in group-3 MB patient tumors and suppression of IDH1 epigenetically reduces c-MYC and downstream DLAT levels in multiple c-MYC amplified cancers. DLAT is a central regulator of cuproptosis (copper-dependent cell death) induced by the copper ionophore elesclomol. DLAT expression in group-3 MB cells correlates with increased sensitivity to cuproptosis. Elesclomol is brain-penetrant and suppresses tumor growth in vivo in multiple 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-3 MB by cuproptosis.
Cancer Cell , résumé, 2025