title: Activation of HER family members in gastric carcinoma cells mediates resistance to MET inhibition.
abstract: BACKGROUND
  Gastric cancer is the second leading cause of cancer mortality in the world. The receptor tyrosine kinase MET is constitutively activated in many gastric cancers and its expression is strictly required for survival of some gastric cancer cells. Thus, MET is considered a good candidate for targeted therapeutic intervention in this type of tumor, and MET inhibitors recently entered clinical trials. One of the major problems of therapies targeting tyrosine kinases is that many tumors are not responsive to treatment or eventually develop resistance to the drugs. Perspective studies are thus mandatory to identify the molecular mechanisms that could cause resistance to these therapies.
  
  
  RESULTS
  Our in vitro and in vivo results demonstrate that, in MET-addicted gastric cancer cells, the activation of HER (Human Epidermal Receptor) family members induces resistance to MET silencing or inhibition by PHA-665752 (a selective kinase inhibitor). We provide molecular evidences highlighting the role of EGFR, HER3, and downstream signaling pathways common to MET and HER family in resistance to MET inhibitors. Moreover, we show that an in vitro generated gastric cancer cell line resistant to MET-inhibition displays overexpression of HER family members, whose activation contributes to maintenance of resistance.
  
  
  CONCLUSIONS
  Our findings predict that gastric cancer tumors bearing constitutive activation of HER family members are poorly responsive to MET inhibition, even if this receptor is constitutively active. Moreover, the appearance of these alterations might also be responsible for the onset of resistance in initially responsive tumors.
authors.affiliation: Institute for Cancer Research and Treatment, University of Torino Medical School, Candiolo (Torino), Italy. simona.corso@ircc.it.
authors.forename: Simona
authors.initials: S
authors.lastname: Corso
authors.forename: Elena
authors.initials: E
authors.lastname: Ghiso
authors.forename: Virna
authors.initials: V
authors.lastname: Cepero
authors.forename: J Rafael
authors.initials: JR
authors.lastname: Sierra
authors.forename: Cristina
authors.initials: C
authors.lastname: Migliore
authors.forename: Andrea
authors.initials: A
authors.lastname: Bertotti
authors.forename: Livio
authors.initials: L
authors.lastname: Trusolino
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Comoglio
authors.forename: Silvia
authors.initials: S
authors.lastname: Giordano
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D017978:Receptors, Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases