Inhibition of c-met with the specific small molecule tyrosine kinase inhibitor SU11274 decreases growth and metastasis formation of experimental human melanoma

I. Kenessey, M. Keszthelyi, Z. Krámer, J. Berta, A. Ádám, J. Dobos, M. Mildner, B. Flachner, S. Cseh, G. Barna, B. Szokol, L. Őrfi, G. Kéri, B. Döme, W. Klepetko, J. Tímár, J. Tóvári

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

The hepatocyte growth factor/scatter factor (HGF/SF) tyrosine kinase (TK) receptor c-Met plays a crucial role in the development of the invasive phenotype of tumors and thus represents an attractive candidate for targeted therapies in a variety of malignancies, including human malignant melanoma (MM). In contrast to what has been shown previously, we were not able to detect any genetic alterations, either in the juxtamembrane- or in the TK-domain of c-Met, in the studied MM cell lines. Nevertheless, c-Met was constitutively active in these cell lines without exogenous HGF/SF stimulation. The active receptor was localized to the adhesion sites of the cells. Addition of the c-Met TK inhibitor SU11274 specifically decreased the phosphotyrosine signal at the focal adhesion sites, which was accompanied by a decrease in cell proliferation as well as an increase in apoptotic cells. In addition, non-apoptotic concentrations of SU11274 significantly reduced the in vitro migratory capacity of MM cells in the modified Boyden-chamber assay. Administration of SU11274 significantly decreased primary tumor growth as well as the capacity for liver colony formation of MM cells in SCID mice. Our study provides the first evidence for an in vivo antitumor activity of SU11274 in a human melanoma xenograft model, and suggests c-Met as a valid target for the therapy of MM. Consequently, SU11274 treatment might represent a useful strategy for controlling melanoma progression and metastasis in patients with MM.

Original languageEnglish
Pages (from-to)332-342
Number of pages11
JournalCurrent Cancer Drug Targets
Volume10
Issue number3
DOIs
Publication statusPublished - 2010

Fingerprint

Experimental Melanomas
Protein-Tyrosine Kinases
Melanoma
Neoplasm Metastasis
Hepatocyte Growth Factor
Growth
Proto-Oncogene Proteins c-met
Cell Line
Neoplasms
Phosphotyrosine
Focal Adhesions
SCID Mice
((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)
Heterografts
Cell Adhesion
Therapeutics
Cell Proliferation
Phenotype
Liver

Keywords

  • C-met
  • Human malignant melanoma
  • Metastasis
  • SU11274
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Cancer Research

Cite this

Inhibition of c-met with the specific small molecule tyrosine kinase inhibitor SU11274 decreases growth and metastasis formation of experimental human melanoma. / Kenessey, I.; Keszthelyi, M.; Krámer, Z.; Berta, J.; Ádám, A.; Dobos, J.; Mildner, M.; Flachner, B.; Cseh, S.; Barna, G.; Szokol, B.; Őrfi, L.; Kéri, G.; Döme, B.; Klepetko, W.; Tímár, J.; Tóvári, J.

In: Current Cancer Drug Targets, Vol. 10, No. 3, 2010, p. 332-342.

Research output: Contribution to journalArticle

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AU - Kéri, G.

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