High-risk
neuroblastoma remains therapeutically challenging to treat, and the mechanisms promoting disease aggression are poorly understood. Here, we show that elevated expression of
dihydrolipoamide S-succinyltransferase (DLST) predicts poor treatment outcome and aggressive disease in patients with
neuroblastoma. DLST is an E2 component of the α-ketoglutarate (αKG)
dehydrogenase complex, which governs the entry of
glutamine into the tricarboxylic acid cycle (TCA) for oxidative decarboxylation. During this irreversible step, αKG is converted into
succinyl-CoA, producing
NADH for oxidative phosphorylation (OXPHOS). Utilizing a zebrafish model of MYCN-driven
neuroblastoma, we demonstrate that even modest increases in DLST expression promote
tumor aggression, while monoallelic dlst loss impedes disease initiation and progression. DLST depletion in human MYCN-amplified
neuroblastoma cells minimally affected
glutamine anaplerosis and did not alter TCA cycle metabolites other than αKG. However, DLST loss significantly suppressed
NADH production and impaired OXPHOS, leading to growth arrest and apoptosis of
neuroblastoma cells. In addition, multiple inhibitors targeting the electron transport chain, including the potent
IACS-010759 that is currently in clinical testing for other
cancers, efficiently reduced
neuroblastoma proliferation in vitro.
IACS-010759 also suppressed
tumor growth in zebrafish and mouse xenograft models of high-risk
neuroblastoma. Together, these results demonstrate that DLST promotes
neuroblastoma aggression and unveils OXPHOS as an essential contributor to high-risk
neuroblastoma. SIGNIFICANCE: These findings demonstrate a novel role for DLST in
neuroblastoma aggression and identify the OXPHOS inhibitor
IACS-010759 as a potential therapeutic strategy for this deadly disease.