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Eur J Haematol ; 95(6): 524-31, 2015 Dec.
Article in English | MEDLINE | ID: mdl-25684098

ABSTRACT

Although imatinib has therapeutic activity for certain subsets of patients with mastocytosis, it is not always curative. Here, molecular mechanisms that confer imatinib resistance to neoplastic mast cells were investigated using an imatinib-sensitive canine neoplastic mast cell line VI-MC carrying a KIT c.1523A>T activating mutation. Two imatinib-resistant sublines were established by culturing VI-MC cells in increasing concentrations of imatinib (1 µM resistant, rVI-MC1; 10 µM resistant, rVI-MC10). Both sublines had a second KIT mutation c.2443G>C. Recombinant KIT with the second mutation was insensitive to 1 µM but sensitive to 10 µM imatinib. The effect of imatinib on the phosphorylation of KIT and its downstream signalling proteins was then examined using these sublines. KIT and ERK were constitutively phosphorylated in both sublines, and their phosphorylation was suppressed by 10 µM imatinib in rVI-MC1 cells. However, KIT but not ERK phosphorylation was suppressed in rVI-MC10 cells. The phosphorylation of ERK in rVI-MC10 cells was also not diminished by the Src family kinase (SFK) inhibitor dasatinib. This second mutation in KIT may play an important role in imatinib resistance in neoplastic mast cells. Furthermore, KIT/SFK-independent activation of ERK would be involved in imatinib resistance when the neoplastic cells are exposed to higher concentrations of imatinib.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm , Imatinib Mesylate/pharmacology , Mastocytosis/genetics , Mutation , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-kit/genetics , Animals , Biomarkers , Cell Line, Tumor , Cell Proliferation/drug effects , DNA Mutational Analysis , Disease Models, Animal , Dogs , Extracellular Signal-Regulated MAP Kinases/metabolism , Mastocytosis/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-kit/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction
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