PRMT5 Inhibitors in Merkel Cell Carcinoma

Abstract

Merkel Cell Carcinoma (MCC) is a rare neuroendocrineskin cancer. Treatment options are limited, and they are largely based on MCC’s similarity to other cancers, rather than original research. Many of these treatments have low efficacy and significant side effects, and the overall prognosis remains bleak. In this thesis, I will propose a new therapeutic strategy for MCC based on chemical inhibition of protein arginine methyltransferase 5 (PRMT5). PRMT5 inhibitors are already being tested in a variety of other solid and liquid tumors to good effect. Our data suggest that PRMT5 inhibitors may be effective in treating a specific subtype of MCC defined by a viral driver and wildtype p53. Treatment inhibits growth in vitro and results in large changes in alternative splicing and more subtle changes in oxidative metabolism. Furthermore, we observe differential alternative splicing of the p53-regulator MDM4, suggesting a possible mechanism for the drug’s greater efficacy in p53-wildtype cell lines.