title: Preclinical evaluation of biomarkers for response monitoring to the MET inhibitor BAY-853474.
abstract: BACKGROUND
  The receptor tyrosine kinase MET contributes to a wide range of biological activities, including survival, proliferation, and metastasis, which play an important role in cancer progression. MET is frequently overexpressed or amplified in a range of malignancies. Therefore, MET is an attractive therapeutic target for treatment of cancer. BAY-853474 is a novel specific MET inhibitor highly effective in preclinical tumor models.
  
  
  OBJECTIVE
  For response monitoring in clinical studies, soluble plasma biomarkers are the most convenient and least invasive choice. Therefore, we sought to identify such biomarkers in xenograft models.
  
  
  RESULTS
  We show that BAY-853474 reduces the tumor burden in U87MG glioblastoma, NCI-H1993 nonsmall cell lung cancer, and HS746T gastric cancer xenograft models. We demonstrate that the dose dependence is reflected by inhibition of MET phosphorylation and that the soluble plasma biomarkers hepatocyte growth factor, vascular endothelial growth factor, and interleukin-8 as well as the MET-ectodomain can be used to monitor the tumor size and response to treatment. Clinical samples, however, show only moderately elevated levels of these biomarker candidates in cancer patients even with MET amplification. We, therefore, established an immunohistochemistry (IHC) protocol to detect MET phosphorylation that is suitable to monitor the effect of BAY-853474 in tumor biopsies.
  
  
  CONCLUSIONS
  IHC-based analysis of target phosphorylation in tumor biopsies is recommended in addition to testing plasma biomarkers for response monitoring.
authors.affiliation: Global Biomarker Research, Bayer Pharma AG, Berlin, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Klotz
authors.forename: Elke
authors.initials: E
authors.lastname: Schmid
authors.forename: Kirsten
authors.initials: K
authors.lastname: Steiner-Hahn
authors.forename: Tanja
authors.initials: T
authors.lastname: Rose
authors.forename: Jenny
authors.initials: J
authors.lastname: Laube
authors.forename: Lars
authors.initials: L
authors.lastname: Roese
authors.forename: David
authors.initials: D
authors.lastname: Henderson
authors.forename: Thomas
authors.initials: T
authors.lastname: Krahn
authors.forename: Oliver
authors.initials: O
authors.lastname: von Ahsen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000097:blood*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005260:Female; D017228:Hepatocyte Growth Factor / Q000097:blood; D006801:Humans; D016209:Interleukin-8 / Q000097:blood; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000473:pathology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000097:blood* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D016209:Interleukin-8; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met