MET exon 14 skipping mutation is a hepatocyte ...
Document type :
Article dans une revue scientifique: Article original
DOI :
PMID :
Title :
MET exon 14 skipping mutation is a hepatocyte growth factor (HGF)-dependent oncogenic driver in vitro and in humanized HGF knock-in mice.
Author(s) :
Fernandes, Marie [Auteur]
Hoggard, B. [Auteur]
Jamme, Philippe [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Paget, Sonia [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Truong, Marie-Jose [Auteur]
Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP]
Grégoire, V. [Auteur]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Vinchent, Audrey [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Descarpentries, C. [Auteur]
Morabito, Angela [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Stanislovas, J. [Auteur]
Farage, E. [Auteur]
Meneboo, Jean-Pascal [Auteur]
Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 [PLBS]
Sebda, Shéhérazade [Auteur]
Genomic @ Lille - PLBS [GO@L]
Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 [PLBS]
Bouchekioua-Bouzaghou, K. [Auteur]
Nollet, M. [Auteur]
Humez, Sarah [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Perera, T. [Auteur]
Fromme, P. [Auteur]
Grumolato, L. [Auteur]
Université de Rouen Normandie [UNIROUEN]
Neuroendocrine, Endocrine and Germinal Differentiation Communication [NorDic]
Figeac, Martin [Auteur]
Genomic @ Lille - PLBS [GO@L]
Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 [PLBS]
Copin, Marie-Christine [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Tulasne, David [Auteur]
Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP]
Cortot, Alexis [Auteur]
Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP]
Kermorgant, S. [Auteur]
Kherrouche, Zoulika [Auteur]
Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP]
Hoggard, B. [Auteur]
Jamme, Philippe [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Paget, Sonia [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Truong, Marie-Jose [Auteur]
Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP]
Grégoire, V. [Auteur]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Vinchent, Audrey [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Descarpentries, C. [Auteur]
Morabito, Angela [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Stanislovas, J. [Auteur]
Farage, E. [Auteur]
Meneboo, Jean-Pascal [Auteur]
Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 [PLBS]
Sebda, Shéhérazade [Auteur]
Genomic @ Lille - PLBS [GO@L]
Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 [PLBS]
Bouchekioua-Bouzaghou, K. [Auteur]
Nollet, M. [Auteur]
Humez, Sarah [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Perera, T. [Auteur]
Fromme, P. [Auteur]
Grumolato, L. [Auteur]
Université de Rouen Normandie [UNIROUEN]
Neuroendocrine, Endocrine and Germinal Differentiation Communication [NorDic]
Figeac, Martin [Auteur]
Genomic @ Lille - PLBS [GO@L]
Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 [PLBS]
Copin, Marie-Christine [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Tulasne, David [Auteur]
Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP]
Cortot, Alexis [Auteur]
Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP]
Kermorgant, S. [Auteur]
Kherrouche, Zoulika [Auteur]
Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP]
Journal title :
Molecular oncology
Pages :
p. 2257-2274
Publication date :
2023-11-01
ISSN :
1878-0261
English keyword(s) :
hepatocyte growth factor
lung cancer
preclinical models
targeted therapies
transcriptomic
tyrosine kinase receptor
lung cancer
preclinical models
targeted therapies
transcriptomic
tyrosine kinase receptor
HAL domain(s) :
Sciences du Vivant [q-bio]
English abstract : [en]
Exon skipping mutations of the MET receptor tyrosine kinase (METex14), increasingly reported in cancers, occur in 3–4% of non–small-cell lung cancer (NSCLC). Only 50% of patients have a beneficial response to treatment ...
Show more >Exon skipping mutations of the MET receptor tyrosine kinase (METex14), increasingly reported in cancers, occur in 3–4% of non–small-cell lung cancer (NSCLC). Only 50% of patients have a beneficial response to treatment with MET-tyrosine kinase inhibitors (TKIs), underlying the need to understand the mechanism of METex14 oncogenicity and sensitivity to TKIs. Whether METex14 is a driver mutation and whether it requires hepatocyte growth factor (HGF) for its oncogenicity in a range of in vitro functions and in vivo has not been fully elucidated from previous preclinical models. Using CRISPR/Cas9, we developed a METex14/WT isogenic model in nontransformed human lung cells and report that the METex14 single alteration was sufficient to drive MET-dependent in vitro anchorage-independent survival and motility and in vivo tumorigenesis, sensitising tumours to MET-TKIs. However, we also show that human HGF (hHGF) is required, as demonstrated in vivo using a humanised HGF knock-in strain of mice and further detected in tumour cells of METex14 NSCLC patient samples. Our results also suggest that METex14 oncogenicity is not a consequence of an escape from degradation in our cell model. Thus, we developed a valuable model for preclinical studies and present results that have potential clinical implication.Show less >
Show more >Exon skipping mutations of the MET receptor tyrosine kinase (METex14), increasingly reported in cancers, occur in 3–4% of non–small-cell lung cancer (NSCLC). Only 50% of patients have a beneficial response to treatment with MET-tyrosine kinase inhibitors (TKIs), underlying the need to understand the mechanism of METex14 oncogenicity and sensitivity to TKIs. Whether METex14 is a driver mutation and whether it requires hepatocyte growth factor (HGF) for its oncogenicity in a range of in vitro functions and in vivo has not been fully elucidated from previous preclinical models. Using CRISPR/Cas9, we developed a METex14/WT isogenic model in nontransformed human lung cells and report that the METex14 single alteration was sufficient to drive MET-dependent in vitro anchorage-independent survival and motility and in vivo tumorigenesis, sensitising tumours to MET-TKIs. However, we also show that human HGF (hHGF) is required, as demonstrated in vivo using a humanised HGF knock-in strain of mice and further detected in tumour cells of METex14 NSCLC patient samples. Our results also suggest that METex14 oncogenicity is not a consequence of an escape from degradation in our cell model. Thus, we developed a valuable model for preclinical studies and present results that have potential clinical implication.Show less >
Language :
Anglais
Peer reviewed article :
Oui
Audience :
Internationale
Popular science :
Non
ANR Project :
Source :
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