title: Targeting of tumor growth and angiogenesis underlies the enhanced antitumor activity of lenvatinib in combination with everolimus.
abstract: The combination of lenvatinib, a multiple receptor tyrosine kinase inhibitor, plus everolimus, a mammalian target of rapamycin (mTOR) inhibitor, significantly improved clinical outcomes versus everolimus monotherapy in a phase II clinical study of metastatic renal cell carcinoma (RCC). We investigated potential mechanisms underlying the antitumor activity of the combination treatment in preclinical RCC models. Lenvatinib plus everolimus showed greater antitumor activity than either monotherapy in three human RCC xenograft mouse models (A-498, Caki-1, and Caki-2). In particular, the combination led to tumor regression in the A-498 and Caki-1 models. In the A-498 model, everolimus showed antiproliferative activity, whereas lenvatinib showed anti-angiogenic effects. The anti-angiogenic activity was potentiated by the lenvatinib plus everolimus combination in Caki-1 xenografts, in which fibroblast growth factor (FGF)-driven angiogenesis may contribute to tumor growth. The combination showed mostly additive activity in vascular endothelial growth factor (VEGF)-activated, and synergistic activity against FGF-activated endothelial cells, in cell proliferation and tube formation assays, as well as strongly suppressed mTOR-S6K-S6 signaling. Enhanced antitumor activities of the combination versus each monotherapy were also observed in mice bearing human pancreatic KP-1 xenografts overexpressing VEGF or FGF. Our results indicated that simultaneous targeting of tumor cell growth and angiogenesis by lenvatinib plus everolimus resulted in enhanced antitumor activity. The enhanced inhibition of both VEGF and FGF signaling pathways by the combination underlies its superior anti-angiogenic activity in human RCC xenograft models.
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Matsuki
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Adachi
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ozawa
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Hoshi
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Okamoto
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Tohyama
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Mitsuhashi
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Atsumi
authors.initials: A
authors.lastname: Yamaguchi
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Matsui
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Funahashi
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004357:Drug Synergism; D000068338:Everolimus / Q000008:administration & dosage / Q000494:pharmacology; D016220:Fibroblast Growth Factor 1 / Q000235:genetics / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D010671:Phenylurea Compounds; D011804:Quinolines; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C531958:lenvatinib
keywords: Combination; everolimus; fibroblast growth factor; lenvatinib; renal cell carcinoma