Targeting PRMT5 to combat cancer drug resistance associated with neuroendocrine differentiation

PROJECT SUMMARY Neuroendocrine Tumors (NETs) occur in multiple organs and share many similarities. Although NETs are relatively rare compared to breast and lung cancers, the incidence of NETs is steadily increasing. Conventional therapies are not effective in treating NETs, and the survival rates of patients with NETs remain low. Trans- differentiation to NETs is suggested as a mechanism of cancer therapy resistance across all epithelial cancers, therefore it is important to understand the initiation and progression of NETs. However, challenges in studying NETs have limited progress in developing therapies. Merkel cell carcinoma (MCC) is a high-grade NET of the skin that is more deadly than melanoma, with about 80% of cases caused by Merkel cell polyomavirus. This type of NET with its viral oncogenic causal factors is thus a valuable model to investigate the biology of NETs. NETs normally exhibit low mutation rates, and epigenetic modifications are hypothesized to be important drivers. In this proposal, we will critically evaluate the role of Protein Arginine Methyltransferase 5 (PRMT5) in MCC as an epigenetic regulator in MCC by investigating PRMT5-mediated arginine methylation that is associated with neuroendocrine differentiation. We hypothesize that PRMT5-mediated histone methylation and downstream targets affected by this methylation are required for the maintenance of NET state of MCC and can additionally affect cancer drug resistance. This project will (1) determine effects of PRMT5 on the NET identity of MCC and drug resistance, and (2) identify PRMT5 targets associated with the NET state of MCC. Inhibitors for PRMT5 are currently in clinical trials for several types of cancer, and understanding the molecular mechanisms of PRMT5 as an epigenetic regulator in MCC will help evaluate the use of PRMT5 inhibitors as a potential therapeutic intervention not only for MCC but also for the treatment of other NETs.