Title :

MET variants with activating N-lobe mutations identified in hereditary papillary renal cell carcinomas still require ligand stimulation.

Author(s) :

Guérin, Célia [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Vinchent, Audrey [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Fernandes, Marie [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Damour, Isabelle [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Laratte, Agathe [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Tellier, Remi [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Estevam, Gabriella O. [Auteur]
University of California [UC]
Meneboo, Jean-Pascal [Auteur]
Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 [PLBS]
Villenet, Celine [Auteur]
Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 [PLBS]
Descarpentries, Clotilde [Auteur]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Fraser, James S. [Auteur]
University of California [San Francisco] [UC San Francisco]
Figeac, Martin [Auteur]
Plateformes Lilloises en Biologie et Santé (PLBS) - UAR 2014 - US 41
Cortot, And Alexis B [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Rouleau, Etienne [Auteur]
Institut Gustave Roussy [IGR]
Tulasne, David [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]

Journal title :

Molecular Oncology

Abbreviated title :

Mol Oncol

Publisher :

FEBS Press

Publication date :

2025-02-22

ISSN :

1878-0261

English keyword(s) :

cancer
hepatocyte growth factor
hereditary papillary renal cancer
MET
receptor tyrosine kinase
somatic mutations

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

In hereditary papillary renal cell carcinoma (HPRCC), the hepatocyte growth factor receptor (MET) receptor tyrosine kinase (RTK) mutations recorded to date are located in the kinase domain and lead to constitutive MET ...
Show more >In hereditary papillary renal cell carcinoma (HPRCC), the hepatocyte growth factor receptor (MET) receptor tyrosine kinase (RTK) mutations recorded to date are located in the kinase domain and lead to constitutive MET activation. This contrasts with MET mutations identified in non-small-cell lung cancer (NSCLC), which lead to exon 14 skipping and deletion of a regulatory domain: In this latter case, the mutated receptor still requires ligand stimulation. Sequencing of MET in samples from 158 HPRCC and 2808 NSCLC patients revealed 10 uncharacterized mutations. Four of these, all found in HPRCC and leading to amino acid substitutions in the N-lobe of the MET kinase, proved able to induce cell transformation, which was further enhanced by hepatocyte growth factor (HGF) stimulation: His1086Leu, Ile1102Thr, Leu1130Ser, and Cis1125Gly. Similar to the variant resulting in MET exon 14 skipping, the two N-lobe MET variants His1086Leu and Ile1102Thr were found to require stimulation by HGF in order to strongly activate downstream signaling pathways and epithelial cell motility. The Ile1102Thr mutation also displayed transforming potential, promoting tumor growth in a xenograft model. In addition, the N-lobe-mutated MET variants were found to trigger a common HGF-stimulation-dependent transcriptional program, consistent with an observed increase in cell motility and invasion. Altogether, this functional characterization revealed that N-lobe variants still require ligand stimulation, in contrast to other RTK variants. This suggests that HGF expression in the tumor microenvironment is important for tumor growth. The sensitivity of these variants to MET inhibitors opens the way for use of targeted therapies for patients harboring the corresponding mutations.Show less >

Language :

Anglais

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

Université de Lille
CHU Lille
CNRS
Inserm
Institut Pasteur de Lille

Collections :

• Plateformes Lilloises en Biologie et Santé (PLBS) - UAR 2014 - US 41

Submission date :

2025-03-11T22:01:43Z
2025-03-19T10:13:25Z