Establishment of a new canine prostate cancer cell line and evaluation of antitumoral effects of BRAF inhibitor and MEK inhibitor combination in canine prostate cancer

抄録

Canine prostate cancer (cPC) is a highly invasive and metastatic malignancy in male dogs, often associated with a poor prognosis despite conventional treatments such as surgery, radiotherapy, and chemotherapy. Notably, the BRAF V595E mutation, orthologous to the human BRAF V600E mutation, is present in 61–80 % of cPC cases and may contribute to tumor progression via activation of the MAPK pathway. While BRAF/MEK dual inhibition has shown clinical efficacy in various human cancers with BRAF mutations, its utility in cPC remains unexplored.

In this study, we established a novel cPC cell line (EPC) derived from a canine patient with BRAF V595E-mutant cPC. EPC demonstrated strong proliferative activity in vitro and tumorigenicity in immunodeficient nude mice. Molecular analysis confirmed the presence of the BRAF V595E mutation. In vitro , EPC exhibited resistance to the BRAF inhibitor dabrafenib, characterized by reactivation of pERK, but this resistance was overcome by the MEK inhibitor trametinib or by combination therapy. The IC ₅₀ values for dabrafenib and trametinib in the combination treatment were approximately 28.1 nM and 2.81 nM, respectively, comparable to clinically achievable concentrations.

EPC is the first BRAF V595E-mutant cPC cell line to demonstrate resistance to BRAF inhibition and sensitivity to MEK inhibition. These findings highlight EPC as a valuable model for studying MAPK pathway-mediated drug resistance and support the potential of dabrafenib/trametinib combination therapy as a novel treatment strategy for cPC.