title: Improved diagnostics targeting c-MET in non-small cell lung cancer: expression, amplification and activation?
abstract: BACKGROUND
  Several c-MET targeting inhibitory molecules have already shown promising results in the treatment of patients with Non-small Cell Lung Cancer (NSCLC). Combination of EGFR- and c-MET-specific molecules may overcome EGFR tyrosine kinase inhibitor (TKI) resistance. The aim of this study was to allow for the identification of patients who might benefit from TKI treatments targeting MET and to narrow in on the diagnostic assessment of MET.
  
  
  METHODS
  222 tumor tissues of patients with NSCLC were analyzed concerning c-MET expression and activation in terms of phosphorylation (Y1234/1235 and Y1349) using a microarray format employing immunohistochemistry (IHC). Furthermore, protein expression and MET activation was correlated with the amplification status by Fluorescence in Situ Hybridization (FISH).
  
  
  RESULTS
  Correlation was observed between phosphorylation of c-MET at Y1234/1235 and Y1349 (spearman correlation coefficient rs = 0.41; p < 0.0001). No significant correlation was shown between MET expression and phosphorylation (p > 0.05). c-MET gene amplification was detected in eight of 214 patients (3.7%). No significant association was observed between c-MET amplification, c-MET protein expression and phosphorylation.
  
  
  CONCLUSIONS
  Our data indicate, that neither expression of c-MET nor the gene amplification status might be the best way to select patients for MET targeting therapies, since no correlation with the activation status of MET was observed. We propose to take into account analyzing the phosphorylation status of MET by IHC to select patients for MET targeting therapies. Signaling of the receptor and the activation of downstream molecules might be more crucial for the benefit of therapeutics targeting MET receptor tyrosine kinases than expression levels alone.
authors.affiliation: Clinical and Experimental Pathology, Research Center Borstel, Borstel, Germany. i.watermann@lungenclinic.de.|LungenClinic Grosshansdorf, Grosshansdorf, Germany. i.watermann@lungenclinic.de.|Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Borstel, Germany. i.watermann@lungenclinic.de.
authors.forename: I
authors.initials: I
authors.lastname: Watermann
authors.affiliation: Clinical and Experimental Pathology, Research Center Borstel, Borstel, Germany.|Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Borstel, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Schmitt
authors.affiliation: Clinical and Experimental Pathology, Research Center Borstel, Borstel, Germany.|Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Borstel, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Stellmacher
authors.affiliation: Clinical and Experimental Pathology, Research Center Borstel, Borstel, Germany.|Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Borstel, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Müller
authors.affiliation: Clinical and Experimental Pathology, Research Center Borstel, Borstel, Germany.|Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
authors.forename: R
authors.initials: R
authors.lastname: Gaber
authors.affiliation: LungenClinic Grosshansdorf, Grosshansdorf, Germany.|Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Borstel, Germany.
authors.forename: Ch
authors.initials: Ch
authors.lastname: Kugler
authors.affiliation: LungenClinic Grosshansdorf, Grosshansdorf, Germany.|Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Borstel, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Reinmuth
authors.affiliation: Ludwig Maximilians University (LMU), Munich, Germany.|Comprehensive Pneumology Center Munich, (CPC-M), Member of the German Center for Lung Research, Thoracic Oncology Centre Munich, Munich, Germany.
authors.forename: R M
authors.initials: RM
authors.lastname: Huber
authors.affiliation: Institute of Pathology, Heidelberg University, Heidelberg, Germany.|Translational Lung Research Center (TLRC), Member of the German Center for Lung Research, Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Medical Clinic, Research Center Borstel, Borstel, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Zabel
authors.affiliation: LungenClinic Grosshansdorf, Grosshansdorf, Germany.|Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Borstel, Germany.
authors.forename: K F
authors.initials: KF
authors.lastname: Rabe
authors.affiliation: Institute of Pathology, Hannover Medical School, Hanover, Germany.|Biomedical Research in Endstage and Obstructive Lung Disease Hanover (BREATH), Member of the German Center for Lung Research, Munich, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Jonigk
authors.affiliation: Institute of Pathology, Heidelberg University, Heidelberg, Germany.|Translational Lung Research Center (TLRC), Member of the German Center for Lung Research, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Warth
authors.affiliation: Clinical and Experimental Pathology, Research Center Borstel, Borstel, Germany.|Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Borstel, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Vollmer
authors.affiliation: Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Borstel, Germany.|Ludwig Maximilians University (LMU), Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Reck
authors.affiliation: Clinical and Experimental Pathology, Research Center Borstel, Borstel, Germany.|Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Borstel, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Goldmann
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods*; D018579:Patient Selection; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D046888:Tissue Array Analysis
chemical_list: D000970:Antineoplastic Agents; D019859:Proto-Oncogene Proteins c-met