Blockade of the pro-fibrotic reaction mediated by the miR-143/-145 cluster enhances the responses to targeted therapy in melanoma.
MAPK inhibitors
fibrosis
melanoma
microRNA
nintedanib
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
07 03 2022
07 03 2022
Historique:
revised:
04
01
2022
received:
16
10
2021
accepted:
10
01
2022
pubmed:
15
2
2022
medline:
15
3
2022
entrez:
14
2
2022
Statut:
ppublish
Résumé
Lineage dedifferentiation toward a mesenchymal-like state displaying myofibroblast and fibrotic features is a common mechanism of adaptive and acquired resistance to targeted therapy in melanoma. Here, we show that the anti-fibrotic drug nintedanib is active to normalize the fibrous ECM network, enhance the efficacy of MAPK-targeted therapy, and delay tumor relapse in a preclinical model of melanoma. Acquisition of this resistant phenotype and its reversion by nintedanib pointed to miR-143/-145 pro-fibrotic cluster as a driver of this mesenchymal-like phenotype. Upregulation of the miR-143/-145 cluster under BRAFi/MAPKi therapy was observed in melanoma cells in vitro and in vivo and was associated with an invasive/undifferentiated profile. The 2 mature miRNAs generated from this cluster, miR-143-3p and miR-145-5p, collaborated to mediate transition toward a drug-resistant undifferentiated mesenchymal-like state by targeting Fascin actin-bundling protein 1 (FSCN1), modulating the dynamic crosstalk between the actin cytoskeleton and the ECM through the regulation of focal adhesion dynamics and mechanotransduction pathways. Our study brings insights into a novel miRNA-mediated regulatory network that contributes to non-genetic adaptive drug resistance and provides proof of principle that preventing MAPKi-induced pro-fibrotic stromal response is a viable therapeutic opportunity for patients on targeted therapy.
Identifiants
pubmed: 35156321
doi: 10.15252/emmm.202115295
pmc: PMC8899916
doi:
Substances chimiques
Carrier Proteins
0
FSCN1 protein, human
0
Indoles
0
MIRN143 microRNA, human
0
MIRN145 microRNA, human
0
MicroRNAs
0
Microfilament Proteins
0
nintedanib
G6HRD2P839
Banques de données
GEO
['GSE171883', 'GSE171880', 'GSE171881', 'GSE171882']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e15295Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.
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