EXTH-76. PRMT5 INHIBITION SENSITIZES GLIOBLASTOMA NEUROSPHERES TO TEMOZOLOMIDE

Abstract INTRODUCTION The median survival of Glioblastoma (GBM) patients is less than two years with the standard care maximal surgical resection, radiation, and temozolomide (TMZ) chemotherapy. Protein Arginine Methyltransferase 5 (PRMT5), which regulates cellular functions by symmetrically di-methylating arginine residues, overexpressed in GBM. Inhibiting PRMT5 induces apoptosis differentiated senescence stem-like GBM tumor cells. We inhibited neurospheres to determine if inhibition would enhance TMZ’s antitumor effect. METHODS depleted activity, vitro, using target-specific siRNA or LLY-283 combined these TMZ treatment. evaluated effect this combination cell viability assay, cycle analysis, western blot. RESULTS reduced GBMNS knockdown significantly more intact GBMNS. elevated expression cleaved caspase 3 caspase3/7 indicating that enhanced apoptotic effects TMZ. Cell analysis showed depleting abrogated TMZ-induced G2/M arrest. Further, treatment PRMT5-depleted increased ɣ-H2AX compared treated TMZ, suggesting depletion DNA damage. also symmetric di-methylation RUVBL1 required for homologous recombination repair treatment-related CONCLUSION Overall, sensitized TMZ-related damage cytotoxicity. These findings support further development potential therapeutic combination.