T-Type calcium channels as potential therapeutic targets in vemurafenib-resistant BRAF melanoma: TTCCs are therapy target in BRAF melanoma.

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.

Concepts Keywords
Apoptosis Biomarker melanoma
Autophagic Tumor burden tumors
Autophagy Stage Targeting melanoma
Biomarker Chemotherapy
Biopsies Radiotherapy
Blockade Medicine
BRAF Clinical medicine
Calcium Branches of biology
Calcium Channel Melanoma
Chemotherapy Genentech
Combination Therapy Cancer treatments
Isoform Sulfonamides
Kinase Vemurafenib
Malignant Targeted therapy
Melanoma BRAF
Melanomas Protein kinase inhibitor
Mutant Apoptosis
Mutation Chemotherapy
Neoplasia
Prognosis
PTEN
Radiotherapy
T Type
Targeted Therapy
Tumor
Vemurafenib
Xenograft

Semantics

Type Source Name
drug DRUGBANK Calcium
drug DRUGBANK Vemurafenib
disease MESH melanoma
pathway KEGG Melanoma
disease MESH neoplasia
pathway KEGG Autophagy
drug DRUGBANK Mibefradil
pathway KEGG Apoptosis

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