biostudies-otherUnknownMs. Serena DiazziKULeuven C1 grantInstitut National de la Santé et de la Recherche Médicale (Inserm)Institut National Du Cancer (INCa)Agence Nationale de la Recherche (ANR)Ligue Contre le Cancer (French League Against Cancer)Centre National de la Recherche Scientifique (CNRS)Canceropôle PACA (Canceropole PACA)Fondation pour la Recherche Médicale (FRM)Fonds Wetenschappelijk Onderzoek (FWO)ITMO Cancer Aviesan Plan CancerFondation ARC pour la Recherche sur le Cancer (ARC)Agence Nationale de la Recherche (ANR) LABEX SIGNALIFEEMBO Molecular Medicinehttps://www.ebi.ac.uk/biostudies/studies/S-SCDT-EMM-2021-15295Lineage dedifferentiation towards a mesenchymal-like state displaying myofibroblast and fibrotic features is a common mechanism of adaptive and 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 pre-clinical 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-143-3pbiostudies-otherINCA_12673ANR-PRCI FIBROMIR(#G.0929.16N18CN045ANR-11-LABX-0028-01Dr. Oskar Marin-BejarDr. Mickael OhannaDr. Bernard MariMr. Julien FassyGeorges VassauxDr. Carine MounierMs. Margaux LecacheurMr. Marin TruchiMs. Alexandrine CarminatiDr. Jean-Christophe MarineMr. Alberto BaeriDr. David GilotFrederic LarbretDr. Christophe GirardDr. Sophie TARTARE-DECKERTDr. Marie IrondelleDr. Caroline LacouxMs. Serena DiazziMs. Lauren LefevreMs. Ilona BerestjukMs. Marie CouraletDr. Marcel DeckertfalseBlockade of the pro-fibrotic reaction mediated by the miR-143/-145 cluster enhances the responses to targeted therapy in melanomaLineage dedifferentiation towards a mesenchymal-like state displaying myofibroblast and fibrotic features is a common mechanism of adaptive and 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 pre-clinical 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-143-3p2022-02-23T00:00:00Z2022-02-23T21:23:01.789Z2022-02-23T21:23:01.789ZS-SCDT-EMM-2021-1529510.15252/emmm.202115295