title: c-Src activation mediates erlotinib resistance in head and neck cancer by stimulating c-Met.
abstract: OBJECTIVE
  Strategies to inhibit the EGF receptor (EGFR) using the tyrosine kinase inhibitor erlotinib have been associated with limited clinical efficacy in head and neck squamous cell carcinoma (HNSCC). Co-activation of alternative kinases may contribute to erlotinib resistance.
  
  
  METHODS
  We generated HNSCC cells expressing dominant-active c-Src (DA-Src) to determine the contribution of c-Src activation to erlotinib response.
  
  
  RESULTS
  Expression of DA-Src conferred resistance to erlotinib in vitro and in vivo compared with vector-transfected control cells. Phospho-Met was strongly upregulated by DA-Src, and DA-Src cells did not produce hepatocyte growth factor (HGF). Knockdown of c-Met enhanced sensitivity to erlotinib in DA-Src cells in vitro, as did combining a c-Met or c-Src inhibitor with erlotinib. Inhibiting EGFR resulted in minimal reduction of phospho-Met in DA-Src cells, whereas complete phospho-Met inhibition was achieved by inhibiting c-Src. A c-Met inhibitor significantly sensitized DA-Src tumors to erlotinib in vivo, resulting in reduced Ki67 labeling and increased apoptosis. In parental cells, knockdown of endogenous c-Src enhanced sensitivity to erlotinib, whereas treatment with HGF to directly induce phospho-Met resulted in erlotinib resistance. The level of endogenous phospho-c-Src in HNSCC cell lines was also significantly correlated with erlotinib resistance.
  
  
  CONCLUSIONS
  Ligand-independent activation of c-Met contributes specifically to erlotinib resistance, not cetuximab resistance, in HNSCC with activated c-Src, where c-Met activation is more dependent on c-Src than on EGFR, providing an alternate survival pathway. Addition of a c-Met or c-Src inhibitor to erlotinib may increase efficacy of EGFR inhibition in patients with activated c-Src.
authors.affiliation: Departments of Pharmacology & Chemical Biology and Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Laura P
authors.initials: LP
authors.lastname: Stabile
authors.forename: Guoqing
authors.initials: G
authors.lastname: He
authors.forename: Vivian Wai Yan
authors.initials: VW
authors.lastname: Lui
authors.forename: Sufi
authors.initials: S
authors.lastname: Thomas
authors.forename: Cassandra
authors.initials: C
authors.lastname: Henry
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Gubish
authors.forename: Sonali
authors.initials: S
authors.lastname: Joyce
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Quesnelle
authors.forename: Jill M
authors.initials: JM
authors.lastname: Siegfried
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004789:Enzyme Activation; D000069347:Erlotinib Hydrochloride; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics*; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D015533:Transcriptional Activation
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D019859:Proto-Oncogene Proteins c-met; D016392:Proto-Oncogene Proteins pp60(c-src)