Distinct interactions between c-Src and c-Met in mediating resistance to c-Src inhibition in head and neck cancer

Clin Cancer Res. 2011 Feb 1;17(3):514-24. doi: 10.1158/1078-0432.CCR-10-1617. Epub 2010 Nov 24.

Abstract

Purpose: 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.

Experimental design: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • CSK Tyrosine-Protein Kinase
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Crizotinib
  • Dasatinib
  • Drug Interactions
  • Drug Resistance, Neoplasm
  • Humans
  • Mice
  • Mice, Nude
  • Mouth Neoplasms / metabolism*
  • Mouth Neoplasms / pathology
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors
  • Proto-Oncogene Proteins c-met / metabolism*
  • Pyrazoles / pharmacology
  • Pyridines / pharmacology
  • Pyrimidines / pharmacology*
  • Thiazoles / pharmacology*
  • src-Family Kinases

Substances

  • Pyrazoles
  • Pyridines
  • Pyrimidines
  • Thiazoles
  • Crizotinib
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-met
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • CSK protein, human
  • Dasatinib