720 Early-stage drug discovery reveals new targets for the treatment of Merkel cell carcinoma

Abstract

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer that lacks durable responses to conventional chemotherapy. Some patients with MCC respond to immune checkpoint inhibitors (ICI), but many show disease progression despite immunotherapy. Patients with immunosuppression or autoimmunity may be precluded from using ICI at all. There are two categories of MCC: virus-positive MCC (VP-MCC) is characterized by integration of the Merkel cell polyomavirus into the host genome and represents the majority of cases, whereas virus-negative MCC (VN-MCC) is associated with mutations induced by ultraviolet light. Our lab aims to identify novel pharmacological targets to treat VP-MCC and VN-MCC. To this end, we screened MCC cell lines against ∼4,000 compounds and identified 39 drugs that suppress viability of MCC relative to control cells. Among these drugs some were effective in all MCC cell lines (n=14), some were VP-MCC specific (n=23), and some were VN-MCC specific (n=2). Top hits were validated with RNA interference (RNAi), and we demonstrated the efficacy of compounds of interest in vivo using xenograft mouse models. These data represent a promising new step toward developing effective novel therapies for MCC.