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Lenvatinib in combination with golvatinib overcomes hepatocyte growth factor pathway-induced resistance to vascular endothelial growth factor receptor inhibitor.

Nakagawa T, Matsushima T, Kawano S, Nakazawa Y, Kato Y, Adachi Y, Abe T, Semba T, Yokoi A, Matsui J, Tsuruoka A, Funahashi Y - Cancer Sci. (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Tsukuba Research Laboratory, Eisai Co., Ltd., Tsukuba, Japan.

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Effect of combination lenvatinib and golvatinib treatment on anti-angiogenic activity in hepatocyte growth factor-expressing human cancer xenograft models in nude mice. (a) Macroscopic photographs of an A2780 s.c. tumor treated with vehicle (control) or combined treatment with lenvatinib and golvatinib. (b) Representative image of CD31 immunohistochemical staining of tumor microvessels in A2780 xenografted tumors in nude mice treated with lenvatinib, golvatinib, or both for 7 days. Bar = 100 μm. (c–e) Quantitative analysis of tumor microvessel density with CD31 staining (c), proliferation index with Ki67 staining (d), and apoptotic cells with TUNEL staining (e) in A2780 xenografted tumors treated with lenvatinib, golvatinib, or both for 7 days. Data represent means ± SD. *P < 0.05 versus control; **P < 0.05 versus the indicated group.
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fig04: Effect of combination lenvatinib and golvatinib treatment on anti-angiogenic activity in hepatocyte growth factor-expressing human cancer xenograft models in nude mice. (a) Macroscopic photographs of an A2780 s.c. tumor treated with vehicle (control) or combined treatment with lenvatinib and golvatinib. (b) Representative image of CD31 immunohistochemical staining of tumor microvessels in A2780 xenografted tumors in nude mice treated with lenvatinib, golvatinib, or both for 7 days. Bar = 100 μm. (c–e) Quantitative analysis of tumor microvessel density with CD31 staining (c), proliferation index with Ki67 staining (d), and apoptotic cells with TUNEL staining (e) in A2780 xenografted tumors treated with lenvatinib, golvatinib, or both for 7 days. Data represent means ± SD. *P < 0.05 versus control; **P < 0.05 versus the indicated group.

Mentions: The surfaces of the A2780 xenograft tumors were reddish, but became pale with combination treatment (Fig.4a). We then tested whether the antitumor effects of combined treatment with lenvatinib and golvatinib were associated with inhibition of tumor angiogenesis in human tumor xenograft models. Consistent with our macroscopic observations, immunohistochemical staining of A2780 xenograft tumors, which were excised from mice treated with compound for 7 days, with antibodies against the endothelial cell marker CD31 demonstrated a decrease in endothelial cell staining with combination treatment (Fig.4b,c) compared with the control or with each treatment individually. Combination treatment also decreased cancer cell proliferation and induced apoptosis of cancer cells (Figs4d,e,S4a,b). Combination treatment also resulted in a significant decrease in tumor microvessel density in the SEKI and KP-4 models, which were treated with compound for 4 days (Fig. S4c,d). Consistent with our in vitro findings, these results suggest that the simultaneous inhibition of VEGFR with lenvatinib and inhibition of Met with golvatinib reduced angiogenesis in the HGF- and VEGF-overexpressing xenograft tumors, resulting in antitumor activity.


Lenvatinib in combination with golvatinib overcomes hepatocyte growth factor pathway-induced resistance to vascular endothelial growth factor receptor inhibitor.

Nakagawa T, Matsushima T, Kawano S, Nakazawa Y, Kato Y, Adachi Y, Abe T, Semba T, Yokoi A, Matsui J, Tsuruoka A, Funahashi Y - Cancer Sci. (2014)

Effect of combination lenvatinib and golvatinib treatment on anti-angiogenic activity in hepatocyte growth factor-expressing human cancer xenograft models in nude mice. (a) Macroscopic photographs of an A2780 s.c. tumor treated with vehicle (control) or combined treatment with lenvatinib and golvatinib. (b) Representative image of CD31 immunohistochemical staining of tumor microvessels in A2780 xenografted tumors in nude mice treated with lenvatinib, golvatinib, or both for 7 days. Bar = 100 μm. (c–e) Quantitative analysis of tumor microvessel density with CD31 staining (c), proliferation index with Ki67 staining (d), and apoptotic cells with TUNEL staining (e) in A2780 xenografted tumors treated with lenvatinib, golvatinib, or both for 7 days. Data represent means ± SD. *P < 0.05 versus control; **P < 0.05 versus the indicated group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317894&req=5

fig04: Effect of combination lenvatinib and golvatinib treatment on anti-angiogenic activity in hepatocyte growth factor-expressing human cancer xenograft models in nude mice. (a) Macroscopic photographs of an A2780 s.c. tumor treated with vehicle (control) or combined treatment with lenvatinib and golvatinib. (b) Representative image of CD31 immunohistochemical staining of tumor microvessels in A2780 xenografted tumors in nude mice treated with lenvatinib, golvatinib, or both for 7 days. Bar = 100 μm. (c–e) Quantitative analysis of tumor microvessel density with CD31 staining (c), proliferation index with Ki67 staining (d), and apoptotic cells with TUNEL staining (e) in A2780 xenografted tumors treated with lenvatinib, golvatinib, or both for 7 days. Data represent means ± SD. *P < 0.05 versus control; **P < 0.05 versus the indicated group.
Mentions: The surfaces of the A2780 xenograft tumors were reddish, but became pale with combination treatment (Fig.4a). We then tested whether the antitumor effects of combined treatment with lenvatinib and golvatinib were associated with inhibition of tumor angiogenesis in human tumor xenograft models. Consistent with our macroscopic observations, immunohistochemical staining of A2780 xenograft tumors, which were excised from mice treated with compound for 7 days, with antibodies against the endothelial cell marker CD31 demonstrated a decrease in endothelial cell staining with combination treatment (Fig.4b,c) compared with the control or with each treatment individually. Combination treatment also decreased cancer cell proliferation and induced apoptosis of cancer cells (Figs4d,e,S4a,b). Combination treatment also resulted in a significant decrease in tumor microvessel density in the SEKI and KP-4 models, which were treated with compound for 4 days (Fig. S4c,d). Consistent with our in vitro findings, these results suggest that the simultaneous inhibition of VEGFR with lenvatinib and inhibition of Met with golvatinib reduced angiogenesis in the HGF- and VEGF-overexpressing xenograft tumors, resulting in antitumor activity.

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.

View Article: PubMed Central - PubMed

Affiliation: Tsukuba Research Laboratory, Eisai Co., Ltd., Tsukuba, Japan.

Show MeSH
Related in: MedlinePlus