T-type calcium channel inhibition restores sensitivity to MAPK inhibitors in de-differentiated and adaptive melanoma cells

• Published in: British journal of cancer Vol. 122; no. 7; pp. 1023 - 1036
• Main Authors: Granados, Karol, Hüser, Laura, Federico, Aniello, Sachindra, Sachindra, Wolff, Gretchen, Hielscher, Thomas, Novak, Daniel, Madrigal-Gamboa, Verónica, Sun, Qian, Vierthaler, Marlene, Larribère, Lionel, Umansky, Viktor, Utikal, Jochen
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.03.2020; Nature Publishing Group UK
• Subjects: Adaptation; Animals; Apoptosis; Calcium channels; Calcium channels (T-type); Calcium Channels, T-Type - genetics; Cell death; Cell differentiation; Cell viability; Disease Models, Animal; Drug resistance; Female; Humans; Kinases; MAP kinase; Melanoma; Melanoma - drug therapy; Melanoma - pathology; Mice; Phenotypes; Phenotypic plasticity; Protein kinase inhibitors; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Raf protein; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-020-0751-8

Drug resistance remains as one of the major challenges in melanoma therapy. It is well known that tumour cells undergo phenotypic switching during melanoma progression, increasing melanoma plasticity and resistance to mitogen-activated protein kinase inhibitors (MAPKi). We investigated the melanoma phenotype switching using a partial reprogramming model to de-differentiate murine melanoma cells and target melanoma therapy adaptation against MAPKi. Here, we show that partially reprogrammed cells are a less proliferative and more de-differentiated cell population, expressing a gene signature for stemness and suppressing melanocyte-specific markers. To investigate adaptation to MAPKi, cells were exposed to B-Raf Proto-Oncogene (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors. De-differentiated cells became less sensitive to MAPKi, showed increased cell viability and decreased apoptosis. Furthermore, T-type calcium channels expression increased in adaptive murine cells and in human adaptive melanoma cells. Treatment with the calcium channel blocker mibefradil induced cell death, differentiation and susceptibility to MAPKi in vitro and in vivo. In summary, we show that partial reprogramming of melanoma cells induces de-differentiation and adaptation to MAPKi. Moreover, we postulated a calcium channel blocker such as mibefradil, as a potential candidate to restore sensitivity to MAPKi in adaptive melanoma cells.