Spleen tyrosine kinase as a novel target in medulloblastoma

Background: Group 3 medulloblastoma (MB) is the most aggressive pediatric brain tumor, characterized by MYC oncogene amplification, poor prognosis, and resistance to standard chemoradiation, necessitating novel therapeutic targets. Spleen Tyrosine Kinase (SYK) is known as an important oncogene and signaling mediator in various hematologic and solid malignancies, contributing to proliferation and survival pathways. Because MYC proteins remain largely undruggable, we investigated SYK as a potential therapeutic target based on its reported cooperation with MYC-driven transcriptional programs in other malignancies. Methods: Since MYC is undruggable, we explored targeting the Spleen Tyrosine Kinase (SYK), a component of MYC-dependent pathways. We used pharmacological inhibition (R406, Bay61, Fostamatinib) in MYC-amplified MB cell lines (HD-MB03 and D425) to assess cell viability and MYC protein levels via MTT assays and Western blotting. We also evaluated the therapeutic potential of SYK inhibition combined with cisplatin in D425 cells. Future work will elucidate the molecular mechanism (transcription/translation) in vitro (via shRNA knockdown, ChIP, RNA sequencing) and evaluate therapeutic efficacy in patient-derived xenograft (PDX) mouse models. Data: SYK inhibition significantly reduced HD-MB03 cell viability in a dose-dependent manner (R406 reduced viability to ~18% at $5 μM) and caused distinct downregulation of MYC protein in both HD-MB03 and D425 cells. Crucially, the combination of SYK inhibitors with the standard chemotherapeutic agent cisplatin showed a synergistic effect in D425 cells, suggesting a potential chemo sensitization mechanism. These preliminary data strongly support the critical role of SYK in MYC-driven MB oncogenesis. Conclusions: The preliminary findings support the hypothesis that SYK acts as a key regulator of MYC-driven tumorigenesis in aggressive medulloblastoma. The observed synergistic toxicity when combining SYK inhibitors with cisplatin in D425 cells highlights a prospective chemo-sensitization mechanism. Targeting the SYK-MYC axis using SYK inhibitors, especially in combination with existing chemotherapies, offers a powerful, clinically translatable strategy to overcome treatment resistance and significantly improve outcomes for patients with high-risk, MYC-driven medulloblastoma