Effect of Tyrosine Kinase Inhibition by Imatinib Mesylate on Mast Cell Tumors in Dogs

Abstract

Background: Imatinib mesylate is a small molecule targeted at dysregulated protein-tyrosine kinase. Mutation of c-kit exon 11, which induces constitutive phosphorylation of KIT, is one of the mechanisms for the development or progression of mast cell tumor (MCT) in dogs. The purpose of this study was to examine the therapeutic potential of imatinib mesylate in canine MCT.Hypothesis: Imatinib mesylate has activity against MCT in dogs, and response to treatment can be correlated to presence of mutation within exon 11 of c-kit.Animals: Twenty-one dogs with MCT with gross tumor burden and median tumor size of 7.2 cm (range, 1.0-25.3 cm) before treatment.Methods: Tumors were analyzed for mutation of c-kit exon 11. Imatinib mesylate was administered PO to the dogs at a dose of 10 mg/kg daily for 1-9 weeks.Results: Ten of 21 dogs (48%) had some beneficial response to imatinib mesylate treatment within 14 days of treatment initiation. All 5 dogs with a demonstrable c-kit mutation in exon 11 responded to the drug (1 complete remission, 4 partial remission).Conclusions and Clinical Importance: Imatinib mesylate has clinical activity against MCT in dogs. Response could not be predicted based on presence of absence of a mutation in exon 11 of c-kit.

Beyond H&E

“…Canine MCTs with activating mutations in exon 11 respond well to TKIs that are now readily available for dogs. 42,47,61,69,111 Furthermore, high-grade MCTs lacking mutations or aberrant KIT expression have been reported to respond better to a chemotherapy protocol composed of vinblastine and prednisone than to TKI. 140 Similar to the results in dogs, cats with MCTs harboring a mutation in exon 8 have also been reported to have a favorable response to TKIs.…”

Successful response to imatinib in two dogs with inoperable grade III infiltrating mast cell tumours: a case report

“…Moreover, other studies reported that several TKIs with different chemical structures from imatinib induced objective tumour regression in canine MCTs with these mutations Hahn et al 2008;London et al 2009). However, several studies reported that clinical activity of imatinib against MCT could not be predicted based on the presence of mutations in exon 8 or 11 of c-kit (Isotani et al 2008;Bonkobara 2015) as in the cases described here.…”

“…Furthermore, in Dog 1, the result of IHC for KIT was strongly positive, supporting the likelihood of aberrantly activated KIT. Considering the recent reports that canine MCT can also be related to other mutations in exons 9, 13, and 17 of c-kit, and the platelet-derived growth factor receptor alpha (PDGFRA) gene, we suggest that future studies should focus on analysis of these genes as well as exons 8 and 11 of c-kit (Isotani et al 2008;Gregory-Bryson et al 2010). …”

“…Recently, tyrosine kinase inhibitors (TKIs) have begun to be used for canine MCTs as a novel targeted therapy (Hahn et al 2008;Isotani et al 2008;London et al 2009;Yamada et al 2011). Many previous studies have demonstrated that response to imatinib, which is a TKI, can be correlated with the presence of mutations in c-kit oncogene exons 8 and 11 found in canine MCT (Kobayashi et al 2012;Nakano et al 2014).…”

Comparação da eficácia do mesilato de imatinibe com a vimblastina associada a prednisona no tratamento do mastocitoma canino: estudo clínico, histopatológico, imunohistoquímico e molecular

“…A menor medida observada nos pacientes que responderam ao tratamento com mesilato de imatinibe foi alcança ao termino das 8 semanas de tratamento resultado diferente do observado por Isotani et al (2008) …”