Abstract 1829: Characterization of factors affecting sensitivity and resistance to PRMT5 inhibition in glioblastoma

Abstract BACKGROUND: Glioblastoma (GBM) is a highly infiltrative and aggressive malignancy with few treatment options; all patients develop recurrence after initial therapy. Due to the dismal outcome of these patients, identification of GBM-specific targets for therapeutic development is urgently needed. PRMT5 is a protein arginine methyltransferase that catalyzes the symmetric dimethylation of arginine residues within histones marks, resulting in chromatin restructuring, which in turn promotes oncogenic processes. PRMT5 inhibition has shown efficacy against multiple malignancies; MTAP loss has been associated with increased sensitivity to PRMT5 inhibitors. Here, we examined the effects of pharmacological abrogation of PRMT5 function using highly specific, brain penetrant, orally bioavailable inhibitors and assessed the role of MTAP and p53 expression on sensitivity to these agents. MATERIALS AND METHODS: Using pharmacological inhibition of PRMT5 using with the highly specific inhibitors PRT808 and PRT811, we examined their effects on apoptosis, cell proliferation, cell cycle distribution, and methylation markers in patient-derived glioma stem-like cells (GSC) with epigenetic and genetic signaling. Additional studies to identify transcriptomic (RNA-seq), and proteomic (RPPA) landscape related to PRMT5 in gliomas are ongoing. RESULTS: PRT808 and PRT811 induced potent reduction of symmetrical dimethylation (SDMA) protein marks in all GSC tested. However, treatment of GSC214 (mutant p53), GSC262 (mutant p53), GSC811 (truncated p53), and GSC11 (wild type p53) showed that wild type and truncated p53-expressing lines (GSC811 and GSC11) were more sensitive than GSC cell lines expressing mutant p53 (GSC214 and GSC262). There was no correlation between MTAP status and sensitivity to PRMT5 inhibition. In addition, PRMT5 inhibition resulted in reduced proliferation and alteration of several cell survival pathways; induction of apoptosis in GSC cell lines at late time points around 8-9 days after single dose treatment even though SDMA reduction occurred as early as 3 days. CONCLUSIONS: Our results demonstrate pharmacological PRMT5 inhibition induced SDMA reduction and late apoptosis in genetically and epigenetically heterogeneous patient-derived GSC lines and that mutant p53 lines are less sensitive to PRMT5 inhibition. Additional studies related to splicing defects upon PRMT5 inhibition are ongoing and will be presented at the meeting. Citation Format: Tsung-Lin (Gavin) Tsai. Characterization of factors affecting sensitivity and resistance to PRMT5 inhibition in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1829.