The Met kinase inhibitor SU11274 exhibits a selective inhibition pattern toward different receptor mutated variants.
Point mutations constitute a major mode of oncogenic activation of the Met receptor tyrosine kinase. Met is aberrantly activated in many types of human malignancies and its deregulated activity is correlated with aggressive tumor traits such as abnormal proliferation and survival, leading to tumor growth, local invasion and metastasis. Here we report that the Met kinase inhibitor SU11274 differentially affects the kinase activity and subsequent signaling of various mutant forms of Met. Two Met variants tested, M1268T and H1112Y, were potently inhibited by 2 microM SU11274, while two other variants, L1213V and Y1248H, remained resistant under similar experimental conditions. Inhibition of the kinase altered cell proliferation, morphology and motility, while cells containing resistant mutants appeared unaffected by the compound. The basis for the sensitivity or resistance to SU11274 is discussed in terms of the position of the mutations predicted from a homology model.
Berthou
Sylvie
S
Department of Radiation Oncology, Inselspital Bern, Switzerland.
Aebersold
Daniel M
DM
Schmidt
Laura S
LS
Stroka
Deborah
D
Heigl
Christine
C
Streit
Bruno
B
Stalder
Denise
D
Gruber
Guenther
G
Liang
Congxin
C
Howlett
Anthony R
AR
Candinas
Daniel
D
Greiner
Richard H
RH
Lipson
Kenneth E
KE
Zimmer
Yitzhak
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle; D002455:Cell Division; D002460:Cell Line; D002465:Cell Movement; D002470:Cell Survival; D004247:DNA / Q000737:chemistry; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D041681:NIH 3T3 Cells; D009362:Neoplasm Metastasis; D010879:Piperazines / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*
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; D004247:DNA; D019859:Proto-Oncogene Proteins c-met