title: High Potency VEGFRs/MET/FMS Triple Blockade by TAS-115 Concomitantly Suppresses Tumor Progression and Bone Destruction in Tumor-Induced Bone Disease Model with Lung Carcinoma Cells.
abstract: Approximately 25-40% of patients with lung cancer show bone metastasis. Bone modifying agents reduce skeletal-related events (SREs), but they do not significantly improve overall survival. Therefore, novel therapeutic approaches are urgently required. In this study, we investigated the anti-tumor effect of TAS-115, a VEGFRs and HGF receptor (MET)-targeted kinase inhibitor, in a tumor-induced bone disease model. A549-Luc-BM1 cells, an osteo-tropic clone of luciferase-transfected A549 human lung adenocarcinoma cells (A549-Luc), produced aggressive bone destruction associated with tumor progression after intra-tibial (IT) implantation into mice. TAS-115 significantly reduced IT tumor growth and bone destruction. Histopathological analysis showed a decrease in tumor vessels after TAS-115 treatment, which might be mediated through VEGFRs inhibition. Furthermore, the number of osteoclasts surrounding the tumor was decreased after TAS-115 treatment. In vitro studies demonstrated that TAS-115 inhibited HGF-, VEGF-, and macrophage-colony stimulating factor (M-CSF)-induced signaling pathways in osteoclasts. Moreover, TAS-115 inhibited Feline McDonough Sarcoma oncogene (FMS) kinase, as well as M-CSF and receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation. Thus, VEGFRs/MET/FMS-triple inhibition in osteoclasts might contribute to the potent efficacy of TAS-115. The fact that concomitant dosing of sunitinib (VEGFRs/FMS inhibition) with crizotinib (MET inhibition) exerted comparable inhibitory efficacy for bone destruction to TAS-115 also supports this notion. In conclusion, TAS-115 inhibited tumor growth via VEGFR-kinase blockade, and also suppressed bone destruction possibly through VEGFRs/MET/FMS-kinase inhibition, which resulted in potent efficacy of TAS-115 in an A549-Luc-BM1 bone disease model. Thus, TAS-115 shows promise as a novel therapy for lung cancer patients with bone metastasis.
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Hidenori
authors.identifier: http://orcid.org/0000-0002-1170-3284
authors.initials: H
authors.lastname: Fujita
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Gomori
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Fujioka
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kataoka
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hashimoto
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Ito
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Haruma
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yamamoto-Yokoi
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Naomoto
authors.initials: N
authors.lastname: Harada
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Motomu
authors.initials: M
authors.lastname: Sakuragi
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Oda
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Matsuo
authors.affiliation: Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, Koganei, Tokyo, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Inada
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yonekura
mesh_terms: D000072283:A549 Cells; D000818:Animals; D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000556:secondary; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000077547:Crizotinib; D004195:Disease Models, Animal; D006801:Humans; D007211:Indoles / Q000627:therapeutic use / Q000633:toxicity; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use* / Q000633:toxicity; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011720:Pyrazoles / Q000627:therapeutic use / Q000633:toxicity; D011725:Pyridines / Q000627:therapeutic use / Q000633:toxicity; D011758:Pyrroles / Q000627:therapeutic use / Q000633:toxicity; D011804:Quinolines / Q000627:therapeutic use* / Q000633:toxicity; D053245:RANK Ligand / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000077210:Sunitinib; D013890:Thiourea / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D013977:Tibia / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D014183:Transplantation, Heterologous; D055114:X-Ray Microtomography
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011758:Pyrroles; D011804:Quinolines; D053245:RANK Ligand; D000077547:Crizotinib; D019859:Proto-Oncogene Proteins c-met; D016186:Receptor, Macrophage Colony-Stimulating Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D013890:Thiourea; C000590217:4-(2-fluoro-4-((((2-phenylacetyl)amino)thioxomethyl)amino)phenoxy)-7-methoxy-N-methyl-6-quinolinecarboxamide; D000077210:Sunitinib