CNSC-31. TARGETING STK17A IN GLIOBLASTOMA: A NOVEL THERAPEUTIC STRATEGY USING BRAIN-PENETRANT INHIBITORS

Abstract For decades, the survival rate for glioblastoma (GBM) has remained nearly stagnant, with a current 5-year survival rate of only 5%. GBM is the most common and lethal primary brain tumor in adults, yet only four FDA-approved drugs have been developed for it over the past century. Its high intratumoral heterogeneity and therapy resistance have made it difficult to identify effective molecular targets. Attempts to target well-known oncogenes, such as the epidermal growth factor receptor (EGFR) and other receptor tyrosine kinases (RTKs), have largely failed in clinical trials. However, our investigation has identified a promising and previously underexplored target: Serine/Threonine Kinase 17A (STK17A), also known as DRAK1. We confirmed STK17A is significantly overexpressed in GBM, particularly in EGFR-amplified and IDH-wildtype tumors, using bulk and single-cell RNA sequencing datasets. High STK17A expression correlated with poor patient prognosis. Despite limited prior characterization, STK17A appears to be involved in cell proliferation, tumorigenesis, and metastasis. To define its role in GBM, we performed genetic silencing of STK17A in GBM cell lines, revealing that STK17A regulates proliferation, cell morphology, and upstream RTK signaling. In particular, spatial transcriptomics showed a close association between STK17A and EGFR expression in patient tissues. STK17A silencing in orthotopic xenograft mouse models significantly extended survival. Building on these findings, we developed a series of novel, selective, brain-penetrant small molecule inhibitors of STK17A. Lead compounds demonstrated strong anti-tumor efficacy, minimal toxicity, and favorable pharmacokinetics. In vivo treatment with these inhibitors reduced tumor burden and improved survival by nearly 40%. Phosphoproteomic and transcriptomic profiling indicated minimal off-target effects, reinforcing the specificity of STK17A inhibition. In conclusion, this study provides the first preclinical validation of STK17A as a therapeutic target in GBM and lays the foundation for the clinical development of STK17A inhibitors as a new strategy for GBM treatment.