DDDR-02. PRMT5 inhibition sensitizes glioblastoma tumor models to temozolomide

Abstract BACKGROUND Glioblastoma shows a dismal prognosis despite the multimodal therapies that include maximal surgical resection, radiation, and chemotherapy. Although temozolomide (TMZ) is the standard chemotherapy for glioblastoma, tumor cells invariably develop resistance to TMZ. Protein arginine methyltransferase 5 (PRMT5) is overexpressed in glioblastoma, and its inhibition imparts an anti-tumor effect. However, the mechanistic role of PRMT5 in treatment-resistant glioblastoma is unknown. METHODS Patient-derived glioma stem-like cells (GSCs), which present different sensitivity to TMZ, were treated with PRMT5 inhibitor (LLY-283) or transfected with PRMT5 target-specific siRNA in combination with TMZ and subjected to in vitro functional and mechanistic studies. The intracranial mouse xenograft model was used to test in vivo antitumor efficacy of combination treatment. RESULTS We found that PRMT5 inhibition enhanced the cytotoxic effect and caspase 3/7 activity of TMZ in GSCs, regardless of their original sensitivity to TMZ. PRMT5 inhibition abrogated the TMZ-induced G2/M cell cycle arrest. Unbiased transcriptomic studies indicate that PRMT5 inhibition negatively enriches DNA damage repair genes. Significantly, combination therapy increased DNA double-strand breaks (γH2AX foci) and enhanced the DNA damage (comet assay), suggesting that the combination treatment increases the TMZ-induced DNA damage. Specifically, the LLY-283 treatment blocked homologous recombination repair in GSCs. In vivo, LLY-283 and TMZ combination significantly curbed the tumor growth and prolonged the survival of tumor-bearing mice. CONCLUSION Concomitant treatment of LLY-283 and TMZ has significantly greater antitumor efficacy, suggesting that PRMT5 inhibition and TMZ combination could be a novel therapeutic strategy for glioblastoma.