title: [MET receptor inhibition: Hope against resistance to targeted therapies?]
abstract: Overcoming the drug resistance remains a crucial issue in cancer treatment. For refractory patients, the use of MET receptor tyrosine kinase inhibitors seems to be hopeful. Indeed, important mechanisms underlying drug resistance argue for association of MET inhibitors with targeted therapies, both on first-line to prevent a primary resistance and on the second line to overcoming acquired resistance. Indeed, met gene amplification is the second most common alteration involved in acquired resistance to anti-epidermal growth factor receptor (EGFR) therapies in non-small cells lung cancer (NSCLC). Hypoxia, for its part, can activate MET transcription and amplifies HGF signaling resulting in MET activation, which could be involved in vascular endothelial growth factor (VEGF) inhibitors escape. In HER2 positive breast cancers, MET amplification may also induce tumor cells a hatch escape, resulting in secondary resistance. Finally, some patients with BRAF mutated melanoma exhibit primary resistance to BRAF inhibition by stromal HGF (ligand of MET) secretion resulting in MET receptor activation. Experimental data highlight the role of MET in primary and secondary resistance and encourage combined treatments including MET inhibitors. In this context, several promising clinical trials are in progress in numerous cancers (NSCLC, melanoma, breast cancer, glioblastoma…) using combination of anti-MET and other specific therapies targeting EGFR, BRAF, VEGF or HER2. This review summarizes the potential benefits that MET inhibition should provide to patients with cancer refractory to targeted therapies.
authors.affiliation: Centre Oscar-Lambret, unité tumorigenèse et résistance aux traitements, 3, rue Frédéric-Combemale, 59000 Lille, France; Université Lille 1, Inserm U908, Cell Plasticity and Cancer (CPAC), SN3, 59000 Lille, France; CHU de Lille, 2, avenue Oscar-Lambret, 59000 Lille, France. Electronic address: audrey.hochart@gmail.com.
authors.forename: Audrey
authors.initials: A
authors.lastname: Hochart
authors.affiliation: Centre Oscar-Lambret, unité tumorigenèse et résistance aux traitements, 3, rue Frédéric-Combemale, 59000 Lille, France; Université Lille 1, Inserm U908, Cell Plasticity and Cancer (CPAC), SN3, 59000 Lille, France; Centre Oscar-Lambret, unité d'onco-pédiatrie, 3, rue Frédéric-Combemale, 59000 Lille, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Leblond
authors.affiliation: Université Lille 1, Inserm U908, Cell Plasticity and Cancer (CPAC), SN3, 59000 Lille, France.
authors.forename: Xuefen
authors.initials: X
authors.lastname: Le Bourhis
authors.affiliation: Centre Oscar-Lambret, unité tumorigenèse et résistance aux traitements, 3, rue Frédéric-Combemale, 59000 Lille, France; Université Lille 1, Inserm U908, Cell Plasticity and Cancer (CPAC), SN3, 59000 Lille, France.
authors.forename: Samuel
authors.initials: S
authors.lastname: Meignan
authors.affiliation: Université Lille, CNRS, institut Pasteur de Lille, UMR 8161 - Mechanisms of Tumorigenesis and Target Therapies (M3T), 1, rue Calmette, BP 447, 59000 Lille, France.
authors.forename: David
authors.initials: D
authors.lastname: Tulasne
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000628:therapy; D002289:Carcinoma, Non-Small-Cell Lung; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D005784:Gene Amplification; D018734:Genes, erbB-2; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000628:therapy; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000628:therapy; D058990:Molecular Targeted Therapy; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D018739:Oncogene Proteins v-erbB / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D018739:Oncogene Proteins v-erbB; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: MET receptor; Resistance; Récepteur MET; Résistance primaire; Résistance secondaire; TKI; Targeted therapy; Thérapie ciblée