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@ARTICLE{Granados:166360,
      author       = {K. Granados$^*$ and L. Hüser$^*$ and A. Federico$^*$ and
                      S. Sachindra$^*$ and G. Wolff and T. Hielscher$^*$ and D.
                      Novak$^*$ and V. Madrigal-Gamboa and Q. Sun$^*$ and M.
                      Vierthaler$^*$ and L. Larribère$^*$ and V. Umansky$^*$ and
                      J. Utikal$^*$},
      title        = {{T}-type calcium channel inhibition restores sensitivity to
                      {MAPK} inhibitors in de-differentiated and adaptive melanoma
                      cells.},
      journal      = {British journal of cancer},
      volume       = {122},
      number       = {7},
      issn         = {1532-1827},
      address      = {Edinburgh},
      publisher    = {Nature Publ. Group},
      reportid     = {DKFZ-2020-02849},
      pages        = {1023 - 1036},
      year         = {2020},
      note         = {#EA:A370#LA:A370#},
      abstract     = {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.},
      cin          = {A370 / C060},
      ddc          = {610},
      cid          = {I:(DE-He78)A370-20160331 / I:(DE-He78)C060-20160331},
      pnm          = {311 - Signalling pathways, cell and tumor biology
                      (POF3-311)},
      pid          = {G:(DE-HGF)POF3-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:32063604},
      pmc          = {pmc:PMC7109069},
      doi          = {10.1038/s41416-020-0751-8},
      url          = {https://inrepo02.dkfz.de/record/166360},
}