title: Imatinib elicited a favorable response in a dog with a mast cell tumor carrying a c-kit c.1523A>T mutation via suppression of constitutive KIT activation.
abstract: Target therapy using the tyrosine kinase inhibitor imatinib is one of the new therapeutic approaches for canine mast cell tumors (MCTs). In the present report, we demonstrate a clinical response to imatinib in a dog with MCT carrying a c-kit c.1523A>T mutation. Moreover, the effect of this mutation on the phosphorylation status of KIT and the inhibitory potency of imatinib on the phosphorylation of the mutant KIT were examined in vitro. A dog with a MCT tumor mass on the right forelimb sole with lymph node metastasis and mastocytemia was treated with imatinib. The MCT mass markedly shrank and mastocytemia became undetectable with 2 weeks of treatment. The lymph node enlarged by metastasis became normal in size with 5 weeks of treatment. From the sequencing analysis of c-kit in tumor cells, a substitution mutation c.1523A>T that alters the amino acid composition (p.Asn508Ile) within the extracellular domain of KIT was identified. The mutant KIT expressed on 293 cells showed ligand-independent phosphorylation and imatinib suppressed this phosphorylation in a dose-dependent manner. From these findings, imatinib was considered to elicit a clinical response in a canine case of MCT via inhibition of the constitutively activated KIT caused by a c-kit c.1523A>T mutation.
authors.affiliation: Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, 1-7-1 Kyonan-cho, Musashino-shi, Tokyo 180-8602, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamada
authors.forename: Masato
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Osamu
authors.initials: O
authors.lastname: Sugisaki
authors.forename: Noriko
authors.initials: N
authors.lastname: Ishii
authors.forename: Keita
authors.initials: K
authors.lastname: Ito
authors.forename: Shiori
authors.initials: S
authors.lastname: Kuroki
authors.forename: Yu
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Mayu
authors.initials: M
authors.lastname: Isotani
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Ono
authors.forename: Tsukimi
authors.initials: T
authors.lastname: Washizu
authors.forename: Makoto
authors.initials: M
authors.lastname: Bonkobara
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D004283:Dog Diseases / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D004285:Dogs; D000068877:Imatinib Mesylate; D008297:Male; D054705:Mastocytoma, Skin / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000662:veterinary*; D010766:Phosphorylation; D010879:Piperazines / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit