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Identification of EPLIN as a novel MYCN-independent target in neuroblastoma and medulloblastoma

ABSTRACT: Neuroblastoma and medulloblastoma are the most common solid tumors in children, with MYC(N) proto-oncogene amplification serving as a key marker of aggressive disease and poor treatment outcomes. However, the complex nature of the challenging MYC(N) protein underscores the urgent need for additional targets and therapies to tackle neuroblastoma and medulloblastoma. In this study, we identified FLIX5, a small compound that exhibits broad toxicity against both neuroblastoma and medulloblastoma cells by inducing apoptosis and ferroptosis. Furthermore, FLIX5 enhances the cholesterol dependency of neuroblastoma cells under conditions where mitochondrial function is impaired. FLIX5 as well synergistically enhances the effectiveness of conventional drugs vincristine and vinorelbine against neuroblastoma cells and patient-derived xenograft organoids. Through proteome integral solubility alteration, computational molecular docking predictions, and cellular thermal shift assays for target identification and validation, FLIX5 revealed EPLIN (Epithelial Protein Lost In Neoplasm) as a previously unexplored drug target. EPLIN functions as a tumor suppressor and plays roles in various cellular processes, including cholesterol uptake and mitochondrial activity. The discovery of FLIX5 targeting EPLIN opens new avenues for addressing the significant challenges posed by neuroblastoma and medulloblastoma, and potentially offering broader applications in other types of cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE275538 | GEO | 2025/07/30

REPOSITORIES: GEO

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