Mutations in the fifth immunoglobulin-like domain of kit are common and potentially sensitive to imatinib mesylate in feline mast cell tumours.
The purpose of the current study was to investigate the mutation status of KIT in feline mast cell tumours (MCTs) and to examine the effects of tyrosine kinase inhibition on the phosphorylation of mutant kit in vitro and in clinical cases of cats. Sequence analysis of KIT identified mutations in 42/62 MCTs (67.7%). The vast majority of the mutations were distributed in exons 8 and 9, both of which encode the fifth immunoglobulin-like domain (IgD) of kit. All five types of kit with a mutation in the fifth IgD were then expressed in 293 cells and examined for phosphorylation status. The mutant kit proteins showed ligand-independent phosphorylation. The tyrosine kinase inhibitor imatinib mesylate suppressed the phosphorylation of these mutant kit proteins in transfectant cells. In a clinical study of 10 cats with MCTs, beneficial response to imatinib mesylate was observed in 7/8 cats that had a mutation in the fifth IgD of kit in tumour cells. Mutations in the fifth IgD of kit thus appear to be common and potentially sensitive to imatinib mesylate in feline MCTs. These data provide an in vivo model for paediatric mastocytosis where mutations in the fifth IgD of kit also occur.
Isotani
Mayu
M
Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan.
Yamada
Osamu
O
Lachowicz
Joshua L
JL
Tamura
Kyoichi
K
Yagihara
Hiroko
H
Fujino
Yasuhito
Y
Ono
Kenichiro
K
Washizu
Tsukimi
T
Bonkobara
Makoto
M
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001483:Base Sequence; D001549:Benzamides; D002371:Cat Diseases / Q000188:drug therapy / Q000235:genetics*; D002415:Cats; D004252:DNA Mutational Analysis / Q000379:methods; D004273:DNA, Neoplasm / Q000235:genetics; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005091:Exons / Q000235:genetics; D000068877:Imatinib Mesylate; D007072:Immunoglobulin D / Q000235:genetics; D008415:Mastocytosis / Q000188:drug therapy / Q000235:genetics / Q000662:veterinary*; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001549:Benzamides; D004273:DNA, Neoplasm; D007072:Immunoglobulin D; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit