title: Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth.
abstract: The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling.
authors.affiliation: Exelixis, Inc., 210 East Grand Ave, South San Francisco, CA 94083, USA. myakes@exelixis.com
authors.forename: F Michael
authors.initials: FM
authors.lastname: Yakes
authors.forename: Jason
authors.initials: J
authors.lastname: Chen
authors.forename: Jenny
authors.initials: J
authors.lastname: Tan
authors.forename: Kyoko
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Yongchang
authors.initials: Y
authors.lastname: Shi
authors.forename: Peiwen
authors.initials: P
authors.lastname: Yu
authors.forename: Fawn
authors.initials: F
authors.lastname: Qian
authors.forename: Felix
authors.initials: F
authors.lastname: Chu
authors.forename: Frauke
authors.initials: F
authors.lastname: Bentzien
authors.forename: Belinda
authors.initials: B
authors.lastname: Cancilla
authors.forename: Jessica
authors.initials: J
authors.lastname: Orf
authors.forename: Andrew
authors.initials: A
authors.lastname: You
authors.forename: A Douglas
authors.initials: AD
authors.lastname: Laird
authors.forename: Stefan
authors.initials: S
authors.lastname: Engst
authors.forename: Lillian
authors.initials: L
authors.lastname: Lee
authors.forename: Justin
authors.initials: J
authors.lastname: Lesch
authors.forename: Yu-Chien
authors.initials: YC
authors.lastname: Chou
authors.forename: Alison H
authors.initials: AH
authors.lastname: Joly
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000813:Anilides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000517:prevention & control*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; D000813:Anilides; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C558660:cabozantinib; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D040301:Vascular Endothelial Growth Factor Receptor-2