title: Distinct interactions between c-Src and c-Met in mediating resistance to c-Src inhibition in head and neck cancer.
abstract: OBJECTIVE
  c-Src inhibition in cancer cells leads to an abrogation of invasion but a variable effect on apoptosis. The pathways downstream of c-Src promoting survival are not well characterized. Because cancer therapy that both decreases invasion and induces significant apoptosis would be ideal, we sought to characterize the mechanisms of resistance to c-Src inhibition.
  
  
  METHODS
  c-Src was inhibited in a panel of oral cancer cell lines and subsequent survival and signaling measured. The interactions between c-Src and c-Met were evaluated using immunoprecitation and an in vitro kinase assay. Cytotoxicity was measured and the Chou-Talalay combination index calculated. An orthotopic model of oral cancer was used to assess the effects of c-Met and c-Src inhibitors.
  
  
  RESULTS
  Inhibition of c-Src resulted in c-Met inhibition in sensitive cells lines, but not in resistant cell lines. Isolated c-Met was a c-Src substrate in both sensitive and resistant cells, but there was no interaction of c-Src and c-Met in intact resistant cells. To examine the biological consequences of this mechanism, we demonstrated synergistic cytotoxicity, enhanced apoptosis, and decreased tumor size with the combination of c-Src and c-Met inhibitors.
  
  
  CONCLUSIONS
  Sustained c-Met activation can mediate resistance to c-Src inhibition. These data suggest that the differences between c-Met and c-Src signaling in sensitive and resistant cells are due to distinct factors promoting or inhibiting interactions, respectively, rather than to intrinsic structural changes in c-Src or c-Met. The synergistic cytotoxic effects of c-Src and c-Met inhibition may be important for the treatment of head and neck cancers.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030-4009, USA.
authors.forename: Banibrata
authors.initials: B
authors.lastname: Sen
authors.forename: Shaohua
authors.initials: S
authors.lastname: Peng
authors.forename: Babita
authors.initials: B
authors.lastname: Saigal
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Williams
authors.forename: Faye M
authors.initials: FM
authors.lastname: Johnson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000081247:CSK Tyrosine-Protein Kinase; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000077547:Crizotinib; D000069439:Dasatinib; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000378:metabolism* / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D019061:src-Family Kinases
chemical_list: D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D013844:Thiazoles; D000077547:Crizotinib; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D000069439:Dasatinib