Sphingosine-1 Phosphate Receptor Modulators Increase In Vitro Melanoma Cell Line Proliferation at Therapeutic Doses Used in Patients with Multiple Sclerosis

Introduction: S1P₁ receptor modulators (S1P₁-RM) are oral disease-modifying therapies (DMTs) for multiple sclerosis (MS). Several authorities have raised doubts that S1P₁-RM are responsible for an increased risk of melanoma in patients with MS. We studied the in vitro effects of S1P₁-RM on different melanoma cell lines to compare the effect of available S1P₁-RM on the proliferation of human melanoma cells. Methods: Four S1P₁-RM were studied which are currently approved for managing MS, namely fingolimod (Gilenya^®), siponimod (Mayzent^®), ozanimod (Zeposia^®), and ponesimod (Ponvory^®). We tested these four drugs at different concentrations, including therapeutic doses (0.5, 1.6, 5.5, 18, and 60 µM), on human melanoma cell lines (501Mel cells, 1205LU cells, and M249R cells) to analyze in vitro cell proliferation monitored with the IncuCyte ZOOM live cell microscope (Essen Bioscience). Results: At therapeutic doses, median confluence increased overall for all lineages: + 122% for ozanimod (p < 0.001), + 71% for ponesimod (p < 0.001), + 67% for siponimod (NS), and + 41% for fingolimod (p = 0.094). Ozanimod- and ponesimod-treated cells increased confluency in 501Mel, 1205LU, and M249R cell lines (p < 0.001). Conclusion: These data suggest an increased proliferation of various melanoma cell lines with S1P₁-RM treatments used at therapeutic concentrations for patients with MS and should raise the question of increased dermatologic surveillance.