Juxtamembrane mutant V560GKit is more sensitive to Imatinib (STI571) compared with wild-type c-kit whereas the kinase domain mutant D816VKit is resistant

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dc.contributor.authorFrost, M.
dc.contributor.authorFerrao, P.
dc.contributor.authorHughes, T.
dc.contributor.authorAshman, L.
dc.date.issued2002
dc.description.abstractImatinib (Glivec; STI571) is an ATP-competitive kinase inhibitor of c-Abl, BCR/ABL, c-Kit, and platelet-derived growth factor receptor. Overexpression or constitutive activation of Kit by mutations have been associated with various malignancies. Mutations in the intracellular juxtamembrane region of Kit (e.g., V560G) are common in gastrointestinal stromal tumors and have been linked to poor prognosis. Mutations in the kinase domain of Kit (e.g., D816V) have been detected in mastocytosis, acute myeloid leukemia, and germ-cell tumors. To determine the sensitivity of Kit mutants to Imatinib in the same cellular background, wild-type Kit (WTKit), V560GKit and D816VKit were expressed in FDC-P1 cells. Growth of FDC(WTKit) was inhibited by Imatinib with GI50 (a concentration of drug at which 50% inhibition of growth occurs) of 0.1-0.2 microM but FDC(V560GKit) were more sensitive to Imatinib with a GI50 of 0.01-0.025 microM and FDC(D816VKit) were resistant to Imatinib with a GI50 greater than 5 microM. The naturally occurring isoforms of c-Kit did not differ in their sensitivity to Imatinib. Immunoprecipitation and Western blot analysis indicated that 1 microM Imatinib reduced phosphorylation of WTKit and completely blocked phosphorylation of V560GKit but did not affect D816VKit phosphorylation. In signaling studies, addition of stem cell factor (SCF) induced phosphorylation of ERK and Akt by WTKit, and ERK, Akt and STAT3 by V560GKit, which were all blocked by Imatinib. Imatinib also blocked the constitutive activation of Akt and STAT3 by V560GKit but had no affect on the constitutive activation of ERK, Akt, and STAT3 by D816VKit. Overall, these findings demonstrate the increased susceptibility of the Kit juxtamembrane mutant, V560G, and the resistance of the kinase domain mutant, D816V, to Imatinib compared with WTKit.
dc.identifier.citationMolecular Cancer Therapeutics, 2002; 1(12):1115-1124
dc.identifier.issn1535-7163
dc.identifier.issn1538-8514
dc.identifier.orcidHughes, T. [0000-0002-0910-3730] [0000-0002-7990-4509]
dc.identifier.urihttp://hdl.handle.net/2440/9697
dc.language.isoen
dc.publisherAmer Assoc Cancer Research
dc.subjectTumor Cells, Cultured
dc.subjectHumans
dc.subjectRetroviridae
dc.subjectBenzamides
dc.subjectPiperazines
dc.subjectPyrimidines
dc.subjectAnnexin A5
dc.subjectDNA-Binding Proteins
dc.subjectTrans-Activators
dc.subjectGranulocyte-Macrophage Colony-Stimulating Factor
dc.subjectProtein Isoforms
dc.subjectAntineoplastic Agents
dc.subjectMicroscopy, Fluorescence
dc.subjectBlotting, Western
dc.subjectPrecipitin Tests
dc.subjectPrognosis
dc.subjectFlow Cytometry
dc.subjectCell Separation
dc.subjectSensitivity and Specificity
dc.subjectSignal Transduction
dc.subjectCell Division
dc.subjectApoptosis
dc.subjectProtein Structure, Tertiary
dc.subjectPhosphorylation
dc.subjectMutation
dc.subjectGenetic Vectors
dc.subjectProto-Oncogene Proteins c-kit
dc.subjectSTAT3 Transcription Factor
dc.subjectImatinib Mesylate
dc.titleJuxtamembrane mutant V560GKit is more sensitive to Imatinib (STI571) compared with wild-type c-kit whereas the kinase domain mutant D816VKit is resistant
dc.typeJournal article
pubs.publication-statusPublished

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