Inhibition of c-Met with the specific small molecule tyrosine kinase inhibitor SU11274 decreases growth and metastasis formation of experimental human melanoma.
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 adhesions 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.
Kenessey
István
I
2nd Institute of Pathology, Semmelweis University, Budapest, Hungary.
Keszthelyi
Magdolna
M
Krámer
Z
Z
Berta
Judit
J
Adám
Attila
A
Dobos
Judit
J
Mildner
Michael
M
Flachner
Beáta
B
Cseh
Sándor
S
Barna
Gábor
G
Szokol
Bálint
B
Orfi
Lászl
L
Kéri
György
G
Döme
Balázs
B
Klepetko
Walter
W
Tímár
J
J
Tóvári
J
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D022001:Focal Adhesions / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000556:secondary; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034622:RNA Interference; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine; D023041:Xenograft Model Antitumor Assays
C478479:((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); D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D010879:Piperazines; D013449:Sulfonamides; D014443:Tyrosine; D019859:Proto-Oncogene Proteins c-met