
Molecular changes associated with the development of resistance to imatinib in an imatinib‐sensitive canine neoplastic mast cell line carrying a KIT c.1523A>T mutation
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.
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Keywords: KIT; dog; imatinib; neoplastic mast cells; resistance
Document Type: Research Article
Publication date: December 1, 2015