Blockade of the pro-fibrotic reaction mediated by the miR-143/-145 cluster enhances the responses to targeted therapy in melanoma

EMBO Mol Med. 2022 Mar 7;14(3):e15295. doi: 10.15252/emmm.202115295. Epub 2022 Feb 14.

Abstract

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.

Keywords: MAPK inhibitors; fibrosis; melanoma; microRNA; nintedanib.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Humans
  • Indoles / pharmacology*
  • Mechanotransduction, Cellular
  • Melanoma* / drug therapy
  • Melanoma* / genetics
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Microfilament Proteins / metabolism
  • Neoplasm Recurrence, Local

Substances

  • Carrier Proteins
  • FSCN1 protein, human
  • Indoles
  • MIRN143 microRNA, human
  • MIRN145 microRNA, human
  • MicroRNAs
  • Microfilament Proteins
  • nintedanib

Associated data

  • GEO/GSE171883
  • GEO/GSE171880
  • GEO/GSE171881
  • GEO/GSE171882