Isocitrate dehydrogenase 1 primes group-3 medulloblastomas for cuproptosis

IF 48.8 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2025-05-15 DOI:10.1016/j.ccell.2025.04.013

Derek Dang, Akash Deogharkar, John McKolay, Kyle S. Smith, Pooja Panwalkar, Simon Hoffman, Wentao Tian, Sunjong Ji, Ana P. Azambuja, Siva Kumar Natarajan, Joanna Lum, Jill Bayliss, Katie Manzeck, Stefan R. Sweha, Erin Hamanishi, Matthew Pun, Diya Patel, Sagar Rau, Olamide Animasahun, Abhinav Achreja, Sriram Venneti

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引用次数: 0

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.

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异柠檬酸脱氢酶1启动组-3髓母细胞瘤治疗铜增生

myc驱动的3组髓母细胞瘤（MBs）是无法治愈的儿童恶性脑癌。为了确定可操作的代谢依赖性，我们在预后不良的3mb组中发现了丙酮酸脱氢酶复合物（PDC） e2亚基二氢脂酰基转乙酰化酶（DLAT）的上调。DLAT由c-MYC诱导，靶向DLAT可降低TCA循环代谢和谷胱甘肽合成。我们还注意到，异柠檬酸脱氢酶1 （IDH1）基因表达在3组MB患者肿瘤中上调，IDH1的抑制在多种c-MYC扩增的癌症中表观遗传地降低了c-MYC和下游DLAT水平。DLAT是铜离子载体埃司氯莫尔诱导的铜细胞凋亡（铜依赖性细胞死亡）的中心调节剂。3组MB细胞中DLAT的表达与铜增生敏感性增加相关。在多种组- 3mb动物模型中，埃来氯莫尔具有脑渗透和抑制肿瘤生长的作用。我们的数据揭示了IDH1/c-MYC依赖性漏洞，该漏洞可调节DLAT水平，并可通过cuprotosis靶向杀死group- 3mb。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.