Activation mutations of human c-KIT resistant to imatinib mesylate are sensitive to the tyrosine kinase inhibitor PKC412
| Autor: | Jennifer J. Clark, Joseph D. Growney, Jennifer Adelsperger, Doriano Fabbro, D. Gary Gilliland, James D. Griffin, Richard Stone |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
STAT3 Transcription Factor
medicine.drug_class Immunology Drug Resistance Biochemistry Piperazines Tyrosine-kinase inhibitor Receptor tyrosine kinase Cell Line Mice hemic and lymphatic diseases STAT5 Transcription Factor medicine Animals Humans Enzyme Inhibitors Phosphorylation Protein kinase C B-Lymphocytes Neoplasia biology Autophosphorylation Imatinib Cell Biology Hematology Protein-Tyrosine Kinases Milk Proteins Staurosporine DNA-Binding Proteins Enzyme Activation Proto-Oncogene Proteins c-kit Pyrimidines Imatinib mesylate Benzamides Mutation Imatinib Mesylate Trans-Activators biology.protein Cancer research Tyrosine kinase medicine.drug |
| Zdroj: | Blood. 106:721-724 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2004-12-4617 |
| Popis: | 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. (Blood. 2005;106:721-724) |
| Databáze: | OpenAIRE |
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