Publication date: Dec 23, 2019
Melanoma is a malignant neoplasia that is highly resistant to chemotherapy and radiotherapy and is associated with poor prognosis in advanced stage. Targeting melanoma that harbors the common BRAF mutation with kinase inhibitors, such as vemurafenib, reduces tumor burden, but these tumors frequently acquire resistance to these drugs. We previously proposed that T-type calcium channel (TTCC) expression may serve as a biomarker for melanoma progression and prognosis, and we showed that TTCC blockers reduce migration and invasion rates due to autophagy blockade only in BRAF-mutant melanoma cells. Here, we demonstrated that high expression of the TTCC Cav3.1 isoform is related to autophagic status in vemurafenib-resistant BRAF-mutant melanoma cells and human biopsies, and in silico analysis revealed an enrichment of Cav3.1 expression in post-treatment melanomas. We also demonstrated that the TTCC blocker mibefradil induces apoptosis and impairs migration/invasion via inhibition of autophagy in resistant melanoma cells and mouse xenograft models. Moreover, we identified an association between PTEN status and Cav3.1 expression in these cells as a marker of sensitivity to combination therapy in resistant cells. Together, our results suggest that TTCC blockers offer a potential targeted therapy in resistant BRAF-mutant melanoma and a therapeutic strategy to reduce progression toward BRAFi resistance.
Barcel’o, C., Sis’o, P., Maiques, O., Garc’ia-Mulero, S., Sanz-Pamplona, R., Navaridas, R., Megino, C., , Felip, , Urdanibia, Eritja, N., Soria, X., Piulats, J.M., Penin, R.M., Dolcet, X., Mat’ias-Guiu, X., Mart’i, R.M., and Maci`a, A. T-Type calcium channels as potential therapeutic targets in vemurafenib-resistant BRAF melanoma: TTCCs are therapy target in BRAF melanoma. 25274. 2019 J Invest Dermatol.
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