Establishment of a BRAF V595E-mutant canine prostate cancer cell line and the antitumor effects of MEK inhibitors against canine prostate cancer |
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| Authors: | Masanori Kobayashi Moe Onozawa Shiho Watanabe Tomokazu Nagashima Kyoichi Tamura Yoshiaki Kubo Akiko Ikeda Kazuhiko Ochiai Masaki Michishita Makoto Bonkobara Masato Kobayashi Tatsuya Hori Eiichi Kawakami |
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| Institution: | 1. Laboratory of Reproduction, School of Veterinary Medicine, Nippon Veterinary and Life Science University, Tokyo, Japan;2. Laboratory of Veterinary Pathology, School of Veterinary Medicine, Nippon Veterinary and Life Science University, Tokyo, Japan;3. Laboratory of Veterinary Clinical Pathology, School of Veterinary Medicine, Nippon Veterinary and Life Science University, Tokyo, Japan;4. Veterinary Medical Teaching Hospital, Nippon Veterinary and Life Science University, Tokyo, Japan;5. Laboratory of Veterinary Hygiene, School of Veterinary Medicine, Nippon Veterinary and Life Science University, Tokyo, Japan;6. Laboratory of Reproduction, School of Veterinary Medicine, Nippon Veterinary and Life Science University, Tokyo, Japan
Japan Institute of Small Animal Reproduction (Bio Art), Tokyo, Japan |
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| Abstract: | Canine prostate cancer (cPCa) is a malignant neoplasm with no effective therapy. The BRAF V595E mutation, corresponding to the human BRAF V600E mutation, is found frequently in cPCa. Activating BRAF mutations are recognized as oncogenic drivers, and blockade of MAPK/ERK phosphorylation may be an effective therapeutic target against BRAF-mutated tumours. The aim of this study was to establish a novel cPCa cell line and to clarify the antitumor effects of MEK inhibitors on cPCa in vitro and in vivo. We established the novel CHP-2 cPCa cell line that was derived from the prostatic tissue of a cPCa patient. Sequencing of the canine BRAF gene in two cPCa cell lines revealed the presence of the BRAF V595E mutation. MEK inhibitors (trametinib, cobimetinib and mirdametinib) strongly suppressed cell proliferation in vitro, and trametinib showed the highest efficacy against cPCa cells with minimal cytotoxicity to non-cancer COPK cells. Furthermore, we orally administered 0.3 or 1.0 mg/kg trametinib to CHP-2 xenografted mice and examined its antitumor effects in vivo. Trametinib reduced tumour volume, decreased phosphorylated ERK levels, and lowered Ki-67 expression in xenografts in a dose-dependent manner. Although no clear adverse events were observed with administration, trametinib-treated xenografts showed osteogenesis that was independent of dosage. Our results indicate that trametinib induces cell cycle arrest by inhibiting ERK activation, resulting in cPCa tumour regression in a dose-dependent manner. MEK inhibitors, in addition to BRAF inhibitors, may be a targeted agent option for cPCa with the BRAF V595E mutation. |
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| Keywords: | BRAF canine MEK inhibitor phosphorylation prostate cancer |
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