Dysregulation of tyrosine kinases and use of imatinib in small animal practice

Bonkobara, Makoto

doi:10.1016/j.tvjl.2014.12.015

Cited by 40 publications

(53 citation statements)

References 84 publications

(95 reference statements)

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“…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.…”

Section: Discussionmentioning

confidence: 59%

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

Kim¹,

Kim²,

Kim³

et al. 2016

Vet. Med. - Czech

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ABSTRACT:Two dogs were presented owing to sudden rapid growth of cutaneous masses greater than 10 cm on the neck and axillary region, respectively. Based on history and results of physical examinations, blood work, fine needle aspiration, histopathological examination, and computed tomography, inoperable grade III infiltrating mast cell tumours were diagnosed. After the initiation of imatinib treatment, the masses markedly shrank and became undetectable within 10 days in both dogs, although none of the tumour specimens showed evidence of mutations in sequencing of c-kit exons 8 and 11. These results suggest that imatinib could be a therapeutic option in patients with surgically inoperable canine mast cell tumours, even those that are histopathologically high grade without c-kit exon 8 or 11 mutations.

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Section: Discussionmentioning

confidence: 59%

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

Kim¹,

Kim²,

Kim³

et al. 2016

Vet. Med. - Czech

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“…In addition to these mutations, several minor mutations (allele frequencies 0.7%‐3.7%) also were identified: c.2579A>G (in exon 18) in all cell lines; c.2513A>G (in exon 18) in parental line VI‐MC and the cVI‐MC1 and trVI‐MC1 sublines; and c.2418G>T (in exon 17), c.2515A>G (in exon 18), and c.2579A>T (in exon 18) in cVI‐MC1 only. No mutation in KIT exon 11, where the mutation is most frequently found in canine MCT (Bonkobara, ), was identified. All of the mutations identified by NGS were missense mutations (Table ).…”

Section: Resultsmentioning

confidence: 99%

“…were analyzed by NGS (Table 1) (Bonkobara, 2015), was identified. All of the mutations identified by NGS were missense mutations (Table 1).…”

Section: Genetic Alterations Of Kit In Vi-mc During Clonal Expansiomentioning

confidence: 99%

Genetic alterations of KIT during clonal expansion and subsequent acquisition of resistance to toceranib in a canine mast cell tumor cell line

Kurita

Miyamoto

Tani

et al. 2019

Vet Pharm & Therapeutics

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One of the potential mechanisms underlying acquired resistance to toceranib in canine mast cell tumor (MCT) is the emergence of a secondary mutation in the KIT gene. Here, genetic alterations of KIT during clonal expansion and subsequent acquisition of resistance to toceranib were investigated in the toceranib‐susceptible canine MCT cell line VI‐MC, which carries a KIT‐activating mutation resulting in a predicted p.(Asn508Ile) amino acid change in the receptor tyrosine kinase protein KIT. Two sublines were cloned from VI‐MC and toceranib‐resistant sublines then were established by continuous exposure to toceranib. The mutation status of KIT in parental VI‐MC and its sublines was investigated using next‐generation sequencing (NGS). Additionally, effects of secondary mutations on toceranib sensitivity in p.(Asn508Ile)‐mutant KIT were examined. KIT secondary mutations, including those encoding p.(Asn679Lys)‐, p.(Asp819Val)‐, and p.(Asp819Gly)‐mutant KIT, that confer toceranib insensitivity to p.(Asn508Ile)‐mutant KIT emerged only in toceranib‐resistant VI‐MCs. These mutations were not detected by NGS in the parental VI‐MC line or in the toceranib‐naive cloned VI‐MCs, although the parental line and sublines exhibited genetic heterogeneity in KIT that may have been caused by genetic evolution during clonal expansion. VI‐MC clones with these secondary mutations in KIT appear to have arisen from subclones during treatment with toceranib rather than being pre‐existing. However, further study using a higher resolution technique will be needed to confirm the developmental mechanism of KIT secondary mutation in canine MCT cells with acquired resistance to toceranib.

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“…In general, it is difficult to use humanized antibody drugs in dogs because of failure of cross‐reactivity . Alternatively, small‐molecule drugs often cross‐react with various species . As EGFR protein overexpression is also observed in 72% of canine TCC, the HER2 and EGFR tyrosine kinase inhibitor lapatinib may be effective in canine TCC.…”

Section: Introductionmentioning

confidence: 99%

Anti‐tumour effect of lapatinib in canine transitional cell carcinoma cell lines

Sakai

Maeda

Saeki

et al. 2018

Vet Comparative Oncology

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Transitional cell carcinoma (TCC) accounts for >90% of canine malignant tumours occurring in urinary bladder, and the prognosis is poor. Our previous study, using RNA sequencing, showed that human epidermal growth factor 2 (HER2) was the most activated upstream regulator related to carcinogenesis in canine TCC. The aim of this study was to examine the anti‐tumour effect of lapatinib, a tyrosine kinase inhibitor of HER2, on canine TCC cell lines in vitro and in vivo. Five canine TCC cell lines (TCCUB, Love, Sora, LCTCC, and MCTCC) were used. Western blotting showed that HER2 protein expression was observed in all of the canine TCC cell lines. Lapatinib inhibited phosphorylation of HER2 and cell growth in a dose‐dependent manner. Cell cycle analyses using flow cytometry showed that lapatinib significantly increased the sub‐G1 and G0/G1 phase fractions and significantly decreased the S and G2/M phase fractions in the cell lines (Sora and TCCUB). For the in vivo experiments, the canine TCC cells (Sora) were subcutaneously injected into nude mice. Six days after inoculation, lapatinib (100 mg/kg) or vehicle was administered daily via intraperitoneal administration for 14 days. Tumour volume was significantly smaller in the lapatinib group compared with the vehicle control group. Histologically, lapatinib significantly increased necrotic areas in the tumour tissues. These findings suggest that lapatinib exerts anti‐tumour effects on canine TCC cells by inhibiting HER2 signalling and inducing cell cycle arrest.

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Dysregulation of tyrosine kinases and use of imatinib in small animal practice

Cited by 40 publications

References 84 publications

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

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

Genetic alterations of KIT during clonal expansion and subsequent acquisition of resistance to toceranib in a canine mast cell tumor cell line

Anti‐tumour effect of lapatinib in canine transitional cell carcinoma cell lines

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