Isocitrate dehydrogenase 1 primes group-3 medulloblastomas for cuproptosis Journal Article

  


Authors: Dang, D.; Deogharkar, A.; McKolay, J.; Smith, K. S.; Panwalkar, P.; Hoffman, S.; Tian, W.; Ji, S.; Azambuja, A. P.; Natarajan, S. K.; Lum, J.; Bayliss, J.; Manzeck, K.; Sweha, S. R.; Hamanishi, E.; Pun, M.; Patel, D.; Rau, S.; Animasahun, O.; Achreja, A.; Ogrodzinski, M. P.; Diessl, J.; Cotter, J.; Hawes, D.; Yang, F.; Doherty, R.; Franson, A. T.; Hanaford, A. R.; Eberhart, C. G.; Raabe, E. H.; Orr, B. A.; Wechsler-Reya, R. J.; Chen, B.; Lyssiotis, C. A.; Shah, Y. M.; Lunt, S. Y.; Banerjee, R.; Judkins, A. R.; Prensner, J. R.; Koschmann, C.; Waszak, S. M.; Nagrath, D.; Simoes-Costa, M.; Northcott, P. A.; Venneti, S.
Article Title: Isocitrate dehydrogenase 1 primes group-3 medulloblastomas for cuproptosis
Abstract: 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. © 2025 Elsevier Inc.
Keywords: controlled study; human cell; genetics; nonhuman; mouse; animal; metabolism; animals; mice; cell death; gene expression; animal experiment; animal model; in vivo study; in vitro study; drug screening; enzymology; pathology; xenograft model antitumor assays; cell line, tumor; gene expression regulation; gene expression regulation, neoplastic; epigenetics; myc protein; medulloblastoma; tumor cell line; upregulation; tumor growth; drug therapy; oncogene c myc; myc protein, human; proto-oncogene proteins c-myc; cerebellar neoplasms; copper; isocitrate dehydrogenase; hydrazines; pediatric brain tumor; citric acid cycle; isocitrate dehydrogenase 1; cerebellum tumor; hydrazine derivative; enzyme repression; cancer metabolism; idh1 protein, human; humans; human; female; article; glutathione metabolism; elesclomol; cuproptosis; protein lipoylation
Journal Title: Cancer Cell
Volume: 43
Issue: 6
ISSN: 1535-6108
Publisher: Cell Press  
Date Published: 2025-01-01
Start Page: 1159
End Page: 1174.e8
Language: English
DOI: 10.1016/j.ccell.2025.04.013
PUBMED: 40378837
PROVIDER: scopus
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-105005195378&doi=10.1016%2fj.ccell.2025.04.013&partnerID=40&md5=7a36eed0d9bc2b0836f8ce6a889db38e
Notes: Article -- Source: Scopus
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