Targeting the epigenetic addiction of Merkel cell carcinoma.

Federico Mauri,Cédric Blanpain

doi:10.15252/emmm.202013347

Abstract

Merkel cell carcinoma (MCC) is a rare but very aggressive neuroendocrine cancer of the skin, with very limited therapeutic options. Although immunotherapy is effective in some cases, there is an unmet need for new therapeutic approaches in MCCs. In this issue of EMBO Molecular Medicine, Leiendecker etal identify a selective vulnerability of MCC for inhibitors of the lysine-specific histone demethylase 1A (LSD1). LSD1 inhibitors promote differentiation of tumor cells toward normal Merkel cell fate, impairing tumor cell growth invivo, and opening new avenues for the treatment of patients with MCC.

Highlights

Merkel cell carcinoma (MCC) is a rare but very aggressive neuroendocrine cancer of the skin, with very limited therapeutic options
Merkel cell carcinoma (MCC), which is thought to arise from Merkel cells, is a relatively rare but very aggressive neuroendocrine cancer of the skin, associated with advanced age and immunosuppression
In 80% of the cases, it is caused by the integration of the Merkel cell polyomavirus (MCV), which promotes tumorigenesis through the cooperation of large T viral antigen, that inactivates the Retinoblastoma tumor suppressor gene, and small T viral antigen that activates the MYCL-EP400 transcriptional complex (Harms et al, 2018)

Summary

Introduction

Merkel cell carcinoma (MCC) is a rare but very aggressive neuroendocrine cancer of the skin, with very limited therapeutic options. Two recent studies, including one published in this issue of EMBO Molecular Medicine and the other recently published in Nature Cell Biology, identified LSD1 inhibition as a new therapeutic strategy to treat MCC (Leiendecker et al, 2020; Park et al, 2020). Using an in vitro drug screen with compounds targeting epigenetic regulators, Leiendecker et al identified an LSD1 inhibitor (LSD1i) as a specific and potent drug impairing the growth of MCV-positive MCC cell lines in vitro, without affecting the growth of skin fibroblasts.

Results

Conclusion