Lenvatinib in combination with golvatinib overcomes hepatocyte growth factor pathway-induced resistance to vascular endothelial growth factor receptor inhibitor.
Bottom Line: Here, we explored the effect of the HGF/Met signaling pathway and its inhibitors on resistance to lenvatinib, a VEGFR inhibitor.This HGF-induced resistance was cancelled when the Met inhibitor, golvatinib, was added with lenvatinib.In s.c. xenograft models based on various tumor cell lines with high HGF expression, treatment with lenvatinib alone showed weak antitumor effects, but treatment with lenvatinib plus golvatinib showed synergistic antitumor effects, accompanied by decreased tumor vessel density.
Affiliation: Tsukuba Research Laboratory, Eisai Co., Ltd., Tsukuba, Japan.Show MeSH
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Mentions: We used the above cell lines to create mouse human tumor xenograft models to test the therapeutic effects of lenvatinib and golvatinib given alone or in combination (Fig.3). A clinically relevant dose of lenvatinib (10 mg/kg) showed significant but weak antitumor activity in all but the KP-4 model (Fig.3). Administration of a clinically relevant dose of golvatinib (100 mg/kg) showed similar antitumor activity to lenvatinib in the SEKI and IM95m models, but showed no antitumor activity in the KP-4 and A2780 models. In contrast, combined treatment with lenvatinib and golvatinib showed significant antitumor activities in all four models examined when compared with the control, and in all but the IM95m model when compared with treatment using each agent alone. The in vivo antitumor activities were synergistic in the SEKI, KP-4, and A2780 models, and additive in the IM95m model. Neither abnormal macroscopic findings nor body weight loss were evident in mice treated with either lenvatinib or golvatinib alone or in combination (Fig. S3).
Affiliation: Tsukuba Research Laboratory, Eisai Co., Ltd., Tsukuba, Japan.