c-Met is a potentially new therapeutic target for treatment of human melanoma

Clin Cancer Res. 2007 Apr 1;13(7):2246-53. doi: 10.1158/1078-0432.CCR-06-0776.


Purpose: c-Met is a receptor tyrosine kinase involved in cell growth, invasion, metastases, and angiogenesis. In this study, we investigated the role of c-Met in melanoma biology using a novel small-molecule tyrosine kinase inhibitor SU11274 and small interfering (si) RNA against the receptor.

Experimental design: The effects of SU11274 and c-Met siRNA were studied on proliferation, apoptosis, differentiation, reactive oxygen species, and intracellular signaling. c-Met mutations were examined, and the expression of c-Met and activated c-Met was studied in nevi, primary, and metastatic melanoma.

Results: c-Met was expressed in 6:7 melanoma cell lines by immunoblotting. SU11274 inhibited cell growth in all melanoma cell lines by 85% to 98% with an IC(50) between 1 and 2.5 mumol/L and caused apoptosis (12-58%) in five out of six cell lines. siRNA against c-Met inhibited proliferation of melanoma cells by 60%. This is the first study that shows that SU11274 and siRNA induced microphthalmia-associated transcription factor (MITF) and several other melanoma differentiation proteins and a morphologically differentiated phenotype. SU11274 also inhibited reactive oxygen species formation and phosphorylation of c-Met receptor, AKT and S-6 kinase by the hepatocyte growth factor. A new missense c-Met mutation N948S was identified in cell lines and R988C in tumor tissue in the juxtamembrane domain of c-Met. It was found that c-Met was expressed in 88% of melanomas and 15% of nevi, and that c-Met (pY1003) was activated in 21% of human melanomas.

Conclusion: These results support the role of c-Met in proliferation, apoptosis, differentiation, and tumor progression of melanoma. SU11274 could be used in the therapeutic inhibition of melanoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Fluorescent Antibody Technique
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • Immunohistochemistry
  • Indoles / pharmacology*
  • Melanoma / drug therapy*
  • Melanoma / metabolism
  • Microphthalmia-Associated Transcription Factor
  • Molecular Sequence Data
  • Mutation
  • Piperazines / pharmacology*
  • Polymerase Chain Reaction
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-met / drug effects
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism*
  • RNA, Small Interfering
  • Reactive Oxygen Species / metabolism
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / metabolism
  • Sulfonamides / pharmacology*
  • Transfection


  • ((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide)
  • Indoles
  • Microphthalmia-Associated Transcription Factor
  • Piperazines
  • Protein Kinase Inhibitors
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Sulfonamides
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met