title: Activation mutations of human c-KIT resistant to imatinib mesylate are sensitive to the tyrosine kinase inhibitor PKC412.
abstract: Constitutively activated forms of the transmembrane receptor tyrosine kinase c-KIT have been associated with systemic mast cell disease, acute myeloid leukemia, and gastrointestinal stromal tumors. Reports of the resistance of the kinase domain mutation D816V to the adenosine triphosphate (ATP)-competitive kinase inhibitor imatinib mesylate prompted us to characterize 14 c-KIT mutations reported in association with human hematologic malignancies for transforming activity in the murine hematopoietic cell line Ba/F3 and for sensitivity to the tyrosine kinase inhibitor PKC412. Ten of 14 c-KIT mutations conferred interleukin 3 (IL-3)-independent growth. c-KIT D816Y and D816V transformed cells were sensitive to PKC412 despite resistance to imatinib mesylate. In these cells, PKC412, but not imatinib mesylate, inhibited autophosphorylation of c-KIT and activation of downstream effectors signal transducer and transcriptional activator 5 (Stat5) and Stat3. Variable sensitivities to PKC412 or imatinib mesylate were observed among other mutants. These findings suggest that PKC412 may be a useful therapeutic agent for c-KIT-positive malignancies harboring the imatinib mesylate-resistant D816V or D816Y activation mutations.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Growney
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Clark
authors.forename: Jennifer
authors.initials: J
authors.lastname: Adelsperger
authors.forename: Richard
authors.initials: R
authors.lastname: Stone
authors.forename: Doriano
authors.initials: D
authors.lastname: Fabbro
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D001549:Benzamides; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D008894:Milk Proteins / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D001549:Benzamides; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D008894:Milk Proteins; D010879:Piperazines; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D019311:Staurosporine; C059539:midostaurin