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 first examined the effects of VEGF and HGF in HUVECs, an in vitro angiogenesis model. Addition of either VEGF or HGF significantly promoted cell proliferation and network formation of capillary-like vessels of HUVECs compared to that observed with vehicle alone (control) (Fig.1b,c). Costimulation with VEGF and HGF enhanced proliferation and tube formation of HUVECs to a significantly greater extent than that obtained with either single treatment (Fig.1b,c), and the networks formed after costimulation were more dense and intricately branched than those induced by either single factor (Fig.1d). We next examined the proliferation-inhibiting activity of lenvatinib, which is a potent VEGFR inhibitor, but not a Met inhibitor (Fig.1a). In HUVECs stimulated with VEGF alone, lenvatinib inhibited proliferation at IC50 1.6 nM and reached a plateau of approximately 80% inhibition (Fig.2a). In comparison, treatment with VEGF plus HGF showed decreased inhibitory activity of lenvatinib (IC50, 5.5 nM; plateau of approximately 60% inhibition), indicating that the HUVECs to which HGF had been added were resistant to lenvatinib.
Affiliation: Tsukuba Research Laboratory, Eisai Co., Ltd., Tsukuba, Japan.