PRMT5: An Emerging Target for Pancreatic Adenocarcinoma

SIMPLE SUMMARY: The burden of pancreatic ductal adenocarcinoma (PDAC) increases with rising incidence, yet 5-year overall survival remains poor at 17%. Routine comprehensive genomic profiling of PDAC only finds 2.5% of patients who may benefit and receive matched targeted therapy. Protein arginine methyltransferase 5 (PRMT5) as an anti-cancer target has gained significant interest in recent years and high levels of PRMT5 protein are associated with worse survival outcomes across multiple cancer types. Inhibition of PRMT5 in pre-clinical models can lead to cancer growth inhibition. However, PRMT5 is involved in multiple cellular processes, thus determining its mechanism of action is challenging. While past reviews on PRMT5 have focused on its role in diverse cellular processes and past research studies have focused mainly on haematological malignancies and glioblastoma, this review provides an overview of the possible biological mechanisms of action of PRMT5 inhibition and its potential as a treatment in pancreatic cancer. ABSTRACT: The overall survival of pancreatic ductal adenocarcinoma (PDAC) remains poor and its incidence is rising. Targetable mutations in PDAC are rare, thus novel therapeutic approaches are needed. Protein arginine methyltransferase 5 (PRMT5) overexpression is associated with worse survival and inhibition of PRMT5 results in decreased cancer growth across multiple cancers, including PDAC. Emerging evidence also suggests that altered RNA processing is a driver in PDAC tumorigenesis and creates a partial dependency on this process. PRMT5 inhibition induces altered splicing and this vulnerability can be exploited as a novel therapeutic approach. Three possible biological pathways underpinning the action of PRMT5 inhibitors are discussed; c-Myc regulation appears central to its action in the PDAC setting. Whilst homozygous MTAP deletion and symmetrical dimethylation levels are associated with increased sensitivity to PRMT5 inhibition, neither measure robustly predicts its growth inhibitory response. The immunomodulatory effect of PRMT5 inhibitors on the tumour microenvironment will also be discussed, based on emerging evidence that PDAC stroma has a significant bearing on disease behaviour and response to therapy. Lastly, with the above caveats in mind, current knowledge gaps and the implications and rationales for PRMT5 inhibitor development in PDAC will be explored.