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Abstract

Background: Understanding the development of resistance to treatments remains as one of the major challenges in melanoma therapy. It is well known that tumor cells undergo phenotype switching during melanoma progression, increasing plasticity and resistance to mitogen-activated protein kinase inhibitors (MAPKi). Therefore, studying melanoma phenotype switching could reveal new targets that could be used to overcome therapy resistance. Methods: A model of partial reprogramming was established to susceptibility of dedifferentiated melanoma cells to treatment with MAPKi in order to find new targets to overcome the resistance to MAPKi. Results: The results of this study show that partially reprogrammed C790 and 4434 cells were less proliferative, more invasive and more dedifferentiated cell population, expressing a gene signature associated with stemness and suppressing melanocyte-specific markers. To investigate the development of resistance to MAPKi, murine and human melanoma cells were exposed to BRAF and MEK inhibitors. Dedifferentiated cells were less sensitive to MAPKi, indicated by increased cell viability and decreased apoptosis. Furthermore, T-type calcium channels were overexpressed in partially reprogrammed C790 and 4434 cells, as well as in human adaptive resistant melanoma cells. Treatment with the calcium channel blocker mibefradil induced cell death, differentiation and susceptibility to MAPKi in vitro and in vivo in human adaptive resistant melanoma cells. Conclusions: The results of this study indicate that partial reprogramming represents an innovative model to study melanoma progression and the development of resistance to MAPKi. Moreover, the use of a calcium channel antagonist, such as mibefradil, enhances the effect of MAPKi, by restoring the sensitivity of resistant melanoma cells.