Identification of CSNK1E and MELK as essential kinases to GBM and as future therapeutic targets (P3.130)

OBJECTIVE: To identify kinases essential to GBM tumor cell survival, test their efficacy in multiple cell lines including primary tumor cells, and mice xenografts. BACKGROUND: Glioblastoma is the most common primary central nervous system tumor, mean survival is 14 months with treatment. There is a need for effective therapy specifically targeting GBM tumor cells while sparing normal brain cells. Our kinase screens revealed CSNK1E & MELK as potential novel therapeutic targets for GBM. DESIGN/METHODS: Cell viability following infection with one of four shRNAs (2 CSNK1E and 2 MELK) was evaluated using CellTiter Blue assay in 10 different GBM immortalized and primary cell lines. Cell death pathway analysis was conducted on U87MG cells using Caspase 3/7 activity assay. Mouse xenografts were generated using LN229/glioblastoma stem cells intracranial injections and treated with IC261 (CSNK1E inhibitor) or DMSO. RESULTS: shRNA screen reveals CSNK1E & MELK as potential essential kinases for GBM survival because they are highly expressed in GBM cells compared to brain tissue & when silenced lead to decrease cell survival. In vitro experiments in GBM immortalized and primary cancer cell lines demonstrate decreased viability of cancer cells when CSNK1E & MELK are silenced using shRNA. In vivo experiments with mouse xenografts of GBM cancer stem cells LN229/GSC with commercially available inhibitors of CSNK1E showed decreased tumor size after 20 days compared to control. CONCLUSIONS: MELK has been indicated in the literature an essential kinase for GBM, and in certain cell lines CSNK1E has proven to be more effective at inducing cell death. CSNK1E is an essential kinase for GBM and is a promising target for GBM treatment due to its effect on decreasing cell viability in numerous cell lines as well as GBM primary cells. Results in vitro are supported by in vivo suppression of tumor cell growth using CSNK1E inhibitors. Disclosure: Dr. Pham has nothing to disclose. Dr. Liang has nothing to disclose. Dr. Sheng has nothing to disclose.