DD-07 * A KINOME RNA INTERFERENCE SCREEN IDENTIFIES NOVEL THERAPEUTIC TARGETS FOR GLIOBLASTOMA

Abstract

Glioblastoma (GBM) is the most common primary central nervous system tumor. Despite aggressive therapies such as surgical resection, chemo- and radiotherapies, the life expectancy and survival rates for GBM patients are still low. There is an urgent need for more effective therapies. We here hypothesized that certain kinases that are essential for GBM cell survival and thereby the better therapeutic targets for GBM remain to be defined. To identify these kinases, we designed and performed a dropout RNA interference (RNAi) screen, in which we revealed a subset of kinases that may selectively control the survival of U87MG glioblastoma cells. We elected to focus on casein kinase 1 epsilon (CSNK1E) and maternal embryonic leucine zipper kinase (MELK), the latter of which has previously been demonstrated as an essential kinase for GBM in other reports. Expression levels of these kinases were also shown to be differentially elevated in GBM cells. Our further experiments confirmed that CSNK1E and MELK were essential for the viability of multiple GBM cell lines (U251, SNB75, LN18, SF268, and LN229) as well as primary GBM cells (VTC002). Intriguingly, our data indicate that depletion of CSNK1E using shRNAs is more effective than that of MELK in most GBM cell lines, making it a promising candidate for future targeted GBM therapy. Furthermore, we revealed that both kinases promote the GBM survival through inhibiting apoptosis. Collectively, our results demonstrate that CSNK1E is a novel therapeutic target for GBM. As such, our future work will involve evaluation of CSNK1E inhibitors in treating GBM in vivo using chemical inhibitors.