Dual Specificity Phosphatase 1 (DUSP1) Provides Mechanistic Link Between Melanoma Cellular Plasticity and Drug Resistance

Abstract: Melanoma cells exhibit phenotypic plasticity that allows transition from a proliferative and differentiated phenotype to a more invasive and undifferentiated or transdifferentiated phenotype often also associated with drug resistance. The mechanisms involved in melanoma phenotype plasticity and its role in drug resistance are not fully understood. We previously demonstrated that the MAPK inhibitors (MAPKi)-resistance phenotype is associated with decreased expression of stem cell proliferation genes and increased expression of MAPK inactivation genes, including dual specificity phosphatases (DUSPs). Several members of the DUSP family genes, specifically DUSP1, -3, -8 and -9, are expressed in primary and metastatic melanoma cell lines and pre-and post BRAFi treated patient tumor cells. Here, we show that was knockdown of DUSP1 or DUSP8 or treatment with BCI, a pharmacological inhibitor of DUSP1/6 decreases the survival of MAPKi-resistant cells and sensitizes them to MAPKi. We also show that nestin, a neural crest stem cell marker, and MAP2, a neuronal differentiation marker, are downregulated in MAPKi-resistant cells whereas GFAP, a glial cell marker, present in both MAPKi-sensitive and -resistant cells. Inhibition of DUSP1/6 upregulated nestin expression in MAPKi-sensitive cells and cells with acquired resistance. In contrast, treatment with BCI caused upregulation of MAP2 in MAPKi-sensitive cells and downregulation of both MAP2 and GFAP in all MAPKi-resistant cell lines. These data suggest that DUSP1/6 are involved in melanoma neuronal transdifferentiation serve as mechanistic link between melanoma drug resistance and melanoma differentiation and targets for treatment of MAPKi-resistant melanoma.