TY  - JOUR
AU  - Granados, Karol
AU  - Hüser, Laura
AU  - Federico, Aniello
AU  - Sachindra, Sachindra
AU  - Wolff, Gretchen
AU  - Hielscher, Thomas
AU  - Novak, Daniel
AU  - Madrigal-Gamboa, Verónica
AU  - Sun, Qian
AU  - Vierthaler, Marlene
AU  - Larribère, Lionel
AU  - Umansky, Viktor
AU  - Utikal, Jochen
TI  - T-type calcium channel inhibition restores sensitivity to MAPK inhibitors in de-differentiated and adaptive melanoma cells.
JO  - British journal of cancer
VL  - 122
IS  - 7
SN  - 1532-1827
CY  - Edinburgh
PB  - Nature Publ. Group
M1  - DKFZ-2020-02849
SP  - 1023 - 1036
PY  - 2020
N1  - #EA:A370#LA:A370#
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:32063604
C2  - pmc:PMC7109069
DO  - DOI:10.1038/s41416-020-0751-8
UR  - https://inrepo02.dkfz.de/record/166360
ER  -