title: Multitargeting strategy using lenvatinib and golvatinib: maximizing anti-angiogenesis activity in a preclinical cancer model.
abstract: Almost all cancers show intrinsic and/or evasive resistance to vascular endothelial growth factor (VEGF) inhibitors by multiple mechanisms. Serum angiopoietin-2 (Ang2) level has been proposed as a potential biomarker of VEGF inhibitor response in several cancers. From these clinical observations, the Ang2 and Tie2 (its receptor) axis has been focused on as a promising target. Here, we show a novel strategy to circumvent the resistance by combining multi-tyrosine kinase inhibitors lenvatinib (VEGF receptor, fibroblast growth factor receptor, and RET inhibitor) and golvatinib (E7050; c-Met, Tie2, and EphB4 inhibitor). Tie2 identifies a highly pro-angiogenic macrophage subset, Tie2-expressing macrophages (TEM). Angi-Tie2 and EphB4-EphrinB2 signaling plays critical roles in pericyte-mediated vessel stabilization. In vitro analyses suggested that golvatinib combined with lenvatinib inhibited pericyte-mediated vessel stabilization and TEM differentiation. In thyroid and endometrial cancer models, golvatinib and lenvatinib inhibited pericyte network development and TEM infiltration, resulting in severe perfusion disorder and massive apoptosis. Body weight loss was tolerable, and no macroscopic change was observed. These preclinical studies suggest that modulation of the tumor microenvironment by a strategic and well-tolerated combination of multi-targeting tyrosine kinase inhibitors may sensitize cancer to VEGF inhibitors.
authors.affiliation: Tsukuba Research Laboratory, Eisai Co., Ltd., Ibaraki, Japan.
authors.forename: Youya
authors.initials: Y
authors.lastname: Nakazawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kawano
authors.forename: Junji
authors.initials: J
authors.lastname: Matsui
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Funahashi
authors.forename: Osamu
authors.initials: O
authors.lastname: Tohyama
authors.forename: Hiroki
authors.initials: H
authors.lastname: Muto
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsushima
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D036388:Ephrin-B2 / Q000378:metabolism; D005260:Female; D006801:Humans; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D036224:Receptor, EphB4 / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D042702:Angiopoietin-2; D036388:Ephrin-B2; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D017468:Receptors, Fibroblast Growth Factor; D042461:Vascular Endothelial Growth Factor A; D020794:Receptor Protein-Tyrosine Kinases; D036224:Receptor, EphB4; D042787:Receptor, TIE-2; D040262:Receptors, Vascular Endothelial Growth Factor; C531958:lenvatinib
keywords: Ang2; angiogenesis; golvatinib; lenvatinib; microenvironment