Abstract 4858: Efficacy of the protein arginine methyltransferase PRMT5 inhibitor GSK591 in glioma stem-like cells

Abstract

Abstract Protein arginine methyltransferase (PRMTs) function as epigenetic regulators of transcription and play a major role in gene regulation. PRMTs are upregulated in gastric, colorectal and lung cancer, and lymphoma and leukemia. PRMT5 is capable of forming symmetric dimethylarginine (SDMA) residues, and has been reported as a therapeutic target in glioblastoma, as its expression has been correlated with tumor grade and progression. In this study, the in vitro therapeutic efficacy of PRMT5 inhibitor GSK591 was investigated in a panel of gliomas stem-like cell (GSC) lines with specific molecular subtypes. Genomic, proteiomic (reverse protein lysate array, RPPA), methylation status and GSC subtype were correlated with drug IC50 to find predictors of drug sensitivity. The efficacy of inhibiting PRMT5 activity was retained at low dose of GSK591 in a small number of GSCs. Western blotting data showed high expression of PRMT5 and multiple bands of SDMAs in most GSCs tested (n=31), indicating PRMT5 enzymatic activity in GSC cell lines. Evidence of PRMT5 inhibition was demonstrated at low doses (< 1.5 uM) in 4 GSC lines (13%) as shown by the total inhibition of SDMA expression in a dose- and time-dependent fashion after GSK591 treatment. The sensitivity of GSK591 correlated with low methylation of multiple genes pretreatment, including MAGI2, EGR2, and DUSP16. In addition, upregulated genes in sensitive GSCs correlated with proliferation signatures using gene set enrichment analyses (GSEA). Together, our study demonstrated that inhibition of PRMT5 activity and its substrate product SDMA correlated with inhibition of tumor growth. These promising in vitro results have led to ongoing experiments to evaluate the efficacy of GSK591 in intracranial xenograft models and the underlying mechanism of sensitivity and resistance to PRMT5 inhibition. Citation Format: Vikram Shaw, Yuji Piao, Soon Young Park, Jianwen Dong, Emmanuel Martinez-Ledesma, Caroline Carrillo, Verlene Henry, Ravesanker Ezhilarasan, Erik Sulman, Veerakumar Balasubramaniyan, John F. de Groot. Efficacy of the protein arginine methyltransferase PRMT5 inhibitor GSK591 in glioma stem-like cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4858.