DDDR-12. THE ROLE OF CASEIN KINASE 1 EPSILON IN TEMOZOLOMIDE SENSITIVITY IN GLIOBLASTOMA STEM CELLS

Abstract

Abstract A major hurdle in effectively treating glioblastoma is the resistance to current chemotherapy temozolomide (TMZ), exhibited intrinsically in glioblastoma stem cells (GSCs). GSCs are a population of tumor cells that are self-renewing, highly resilient and capable of forming genetically heterogeneous and difficult-to-treat tumors. Therefore, overcoming TMZ resistance holds significant promise in the treatment of glioblastoma. Casein kinase 1 ε (CK1ε) has been identified as a stem cell factor that is important for GSCs to self-renew. However, whether CK1ε confers TMZ resistance in GSCs remains elusive. METHODS To test the role of CK1ε in the chemoresistance of GSCs, we treated GSC adherent cell lines with TMZ, CK1ε inhibitor IC261, and a combination of TMZ plus IC261. Cell viability was assessed with MTS viability assay or CellTiter-Blue viability assay. RESULTS Cell viability was significantly decreased in GSCs treated with 0.8μM IC261 combined with 100μM TMZ as compared to cells treated with either 0.8μM IC261 or 100μM TMZ alone (p < 0.05). We assessed synergistic drug effects using the Bliss independence model to yield Excess Over Bliss (EOB) scores. EOB > 0% indicates a synergistic effect; EOB = 0% indicates additive effect; and EOB < 0% indicates antagonistic effect. Cells treated with 0.8μM IC261 together with 100μM TMZ yielded EOB of > 0%. CONCLUSIONS Previous work has identified CK1ε as an important stem cell factor in the survival GSCs, but there lacked studies testing the role of CK1ε in TMZ chemoresistance in vitro. We demonstrate synergistic inhibition of cell viability in GSCs treated with CK1ε inhibitor IC261 in combination with TMZ. Based on these results, CK1ε is suggested to play an important role in the chemoresistance of GSCs to TMZ.