title: 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.
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.
authors: Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Kyonan-cho, Musashino-shi, Tokyo, Japan.
authors: Masato
authors: M
authors: Kobayashi
authors: Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Kyonan-cho, Musashino-shi, Tokyo, Japan.
authors: Shiori
authors: S
authors: Kuroki
authors: Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Kyonan-cho, Musashino-shi, Tokyo, Japan.
authors: Yu
authors: Y
authors: Tanaka
authors: Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Kyonan-cho, Musashino-shi, Tokyo, Japan.
authors: Yukari
authors: Y
authors: Moriya
authors: Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Kyonan-cho, Musashino-shi, Tokyo, Japan.
authors: Yukari
authors: Y
authors: Kozutumi
authors: Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Kyonan-cho, Musashino-shi, Tokyo, Japan.
authors: Yuji
authors: Y
authors: Uehara
authors: Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Kyonan-cho, Musashino-shi, Tokyo, Japan.|Japan Animal Referral Medical Center, Kuji, Takatsu-ku, Kawasaki-shi, Kanagawa, Japan.
authors: Kenichiro
authors: K
authors: Ono
authors: Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Kyonan-cho, Musashino-shi, Tokyo, Japan.
authors: Kyoichi
authors: K
authors: Tamura
authors: Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Kyonan-cho, Musashino-shi, Tokyo, Japan.
authors: Tsukimi
authors: T
authors: Washizu
authors: Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Kyonan-cho, Musashino-shi, Tokyo, Japan.
authors: Makoto
authors: M
authors: Bonkobara
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D004285:Dogs; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D008415:Mastocytosis / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: KIT; dog; imatinib; neoplastic mast cells; resistance