title: Met interacts with EGFR and Ron in canine osteosarcoma.
abstract: The receptor tyrosine kinase (RTK) Met is known to be over-expressed in canine osteosarcoma (OSA). In human cancers, the RTKs Met, epidermal growth factor receptor (EGFR) and Ron are frequently co-expressed and engage in heterodimerization, altering signal transduction and promoting resistance to targeted therapeutics. We found that EGFR and Ron are expressed in canine OSA cell lines and primary tissues, EGFR and Ron are frequently phosphorylated in OSA tumour samples, and Met is co-associated with EGFR and Ron in canine OSA cell lines. Transforming growth factor alpha (TGFα) and hepatocyte growth factor (HGF) stimulation induced amplification of ERK1/2 and STAT3 phosphorylation in OSA cells and Met was phosphorylated following TGFα stimulation providing evidence for receptor cross-talk. Lastly, treatment of OSA cells with combined gefitinib and crizotinib inhibited cell proliferation in an additive manner. Together, these data support the notion that Met, EGFR and Ron interact in OSA cells and as such, may represent viable targets for therapeutic intervention.
authors.affiliation: Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: McCleese
authors.forename: M D
authors.initials: MD
authors.lastname: Bear
authors.forename: S K
authors.initials: SK
authors.lastname: Kulp
authors.forename: C
authors.initials: C
authors.lastname: Mazcko
authors.forename: C
authors.initials: C
authors.lastname: Khanna
authors.forename: C A
authors.initials: CA
authors.lastname: London
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D004283:Dog Diseases / Q000378:metabolism; D004285:Dogs; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D012516:Osteosarcoma / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D059467:Transcriptome; D016211:Transforming Growth Factor alpha / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D011518:Proto-Oncogene Proteins; D016211:Transforming Growth Factor alpha; D017228:Hepatocyte Growth Factor; D066246:ErbB Receptors; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases