Introduction

Canine histiocytic sarcoma (CHS) is characterized by aggressive biological behavior, and the establishment of effective chemotherapy for this disease is needed. In our previous study, the FGFR1-ERK/Akt pathway was suggested to be activated in CHS tissues, but not all CHS cell lines were sensitive to single administrations of FGFR1 inhibitors. We hypothesized that the antitumor effect would be enhanced by co-administration of drugs targeting FGFR1-ERK/Akt pathway in CHS cell lines.

Methods

Three molecular targeted drugs against FGFR1-ERK/Akt pathway, dasatinib, trametinib, and ponatinib, were selected to investigate antitumor effects in ten CHS cell lines. Enhancements of inhibitions of cell proliferation by co-administrations of two drugs were evaluated using combination index, an index of pharmacodynamic drug interactions. Changes in protein phosphorylation involved in the ERK/Akt pathway were evaluated using Western blotting.

Results

In two of the ten cell lines, co-administration of drugs was not examined because they were sensitive to the single administration of dasatinib (IC50: 10.6/50.6 nM). In the other eight cell lines, co-administration of dasatinib and trametinib showed the highest synergic effects with CI values ranging from 0.01–1.01. Decreases of both phosphorylated ERK and Akt were observed when synergic effects were observed by co-administration of these drugs.

Conclusion

In CHS, the co-administration of dasatinib and trametinib enhanced the antitumor effect compared to single administrations through inhibiting ERK/Akt activities. Further studies are needed to investigate the efficacies and adverse events of the co-administration in CHS cases.