Selinexor is a novel inhibitor of DNA damage response in Merkel cell carcinoma

Selinexor downregulates DNA damage response (DDR) protein expression with Merkel cell polyomavirus (MCPyV)-negative and MCPyV-positive cell lines. Addition of selinexor alone or combined with immune checkpoint inhibitors (ICIs) may be a promising treatment for Merkel cell carcinoma (MCC). However, further research with selinexor on ICI-recalcitrant MCC cells and clinical trials are required to validate these findings.

Summary

Merkel cell carcinoma (MCC) is a highly lethal cutaneous carcinoma, which in ~80% of cases in the USA is aetiologically linked to Merkel cell polyomavirus (MCPyV). Immune checkpoint inhibitors (ICIs) can successfully treat ~50% of patients with metastatic MCC, but some MCCs are refractory to ICIs, possibly due to altered DNA damage response (DDR). Selinexor, an anticancer therapy that is currently approved in combination with chemotherapy for multiple myeloma, downregulates the small T and large T tumour antigens in MCC through selective inhibition of nuclear exportin 1 (XPO1). We examined the effect of varying doses of selinexor on DDR protein expression in MCPyV-positive and MCPyV-negative MCC cells. Selinexor was found to inhibit DDR protein expression in both MCPyV-positive and MCPyV-negative cells. Addition of selinexor alone or combined with ICI may be a promising treatment for MCC, but further in?vivo research and clinical trials are required to validate these findings.