4.7 Article

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

期刊

EMBO MOLECULAR MEDICINE
卷 14, 期 3, 页码 -

出版社

WILEY
DOI: 10.15252/emmm.202115295

关键词

fibrosis; MAPK inhibitors; melanoma; microRNA; nintedanib

资金

  1. Institut National de la Sante et de la Recherche Medicale (Inserm)
  2. Centre National de la Recherche Scientifique (CNRS)
  3. Ligue Contre le Cancer
  4. Fondation ARC
  5. Institut National du Cancer [INCA_12673]
  6. ITMO Cancer Aviesan (Alliance Nationale pour les Sciences de la Vie et de la Sante, National Alliance for Life Science and Health) [18CN045]
  7. French Government (National Research Agency, ANR) through the Investments for the Future LABEX SIGNALIFE [ANR-11-LABX-0028-01, ANR-PRCI-18-CE92-0009-01 FIBROMIR]
  8. Conseil General 06
  9. Canceropole PACA
  10. Region Provence Alpes Cote d'Azur
  11. LABEX SIGNALIFE
  12. Fondation pour la Recherche Medicale
  13. La Ligue Contre le Cancer
  14. FWO [G.0929.16N]
  15. KULeuven

向作者/读者索取更多资源

This study demonstrates that the anti-fibrotic drug nintedanib can normalize the fibrous ECM network, enhance the effectiveness of MAPK-targeted therapy, and delay tumor relapse in a preclinical model of melanoma. The miR-143/-145 pro-fibrotic cluster plays a crucial role in the acquisition of drug resistance, and the mature miRNAs, miR-143-3p and miR-145-5p, mediate the transition towards a drug-resistant undifferentiated mesenchymal-like state. Preventing the pro-fibrotic stromal response induced by MAPKi treatment presents a viable therapeutic opportunity for melanoma patients.
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.

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