Open AccessZEB 1‐mediated melanoma cell plasticity enhances resistance to MAPK inhibitors
Author(s) -
Richard Geoffrey,
Dalle Stéphane,
Monet MarieAmbre,
Ligier Maud,
Boespflug Amélie,
Pommier Roxane M,
Fouchardière Arnaud,
PerierMuzet Marie,
Depaepe Lauriane,
Barnault Romain,
Tondeur Garance,
Ansieau Stéphane,
Thomas Emilie,
Bertolotto Corine,
Ballotti Robert,
Mourah Samia,
Battistella Maxime,
Lebbé Céleste,
Thomas Luc,
Puisieux Alain,
Caramel Julie
Publication year - 2016
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201505971
Subject(s) - humanities , medicine , art
Abstract Targeted therapies with MAPK inhibitors ( MAPK i) are faced with severe problems of resistance in BRAF ‐mutant melanoma. In parallel to the acquisition of genetic mutations, melanoma cells may also adapt to the drugs through phenotype switching. The ZEB 1 transcription factor, a known inducer of EMT and invasiveness, is now considered as a genuine oncogenic factor required for tumor initiation, cancer cell plasticity, and drug resistance in carcinomas. Here, we show that high levels of ZEB 1 expression are associated with inherent resistance to MAPK i in BRAF V600 ‐mutated cell lines and tumors. ZEB 1 levels are also elevated in melanoma cells with acquired resistance and in biopsies from patients relapsing while under treatment. ZEB 1 overexpression is sufficient to drive the emergence of resistance to MAPK i by promoting a reversible transition toward a MITF low /p75 high stem‐like and tumorigenic phenotype. ZEB 1 inhibition promotes cell differentiation, prevents tumorigenic growth in vivo , sensitizes naive melanoma cells to MAPK i, and induces cell death in resistant cells. Overall, our results demonstrate that ZEB 1 is a major driver of melanoma cell plasticity, driving drug adaptation and phenotypic resistance to MAPK i.