title: Vandetanib inhibits both VEGFR-2 and EGFR signalling at clinically relevant drug levels in preclinical models of human cancer.
abstract: Vandetanib is a multi-targeted receptor tyrosine kinase inhibitor that is in clinical development for the treatment of solid tumours. This preclinical study examined the inhibition of two key signalling pathways (VEGFR-2, EGFR) at drug concentrations similar to those achieved in the clinic, and their contribution to direct and indirect antitumour effects of vandetanib. For in vitro studies, receptor phosphorylation was assessed by Western blotting and ELISA, cell proliferation was assessed using a cell viability endpoint, and effects on cell cycle determined using flow cytometry. For in vivo studies, Western blotting, ELISA and immunohistochemistry (IHC) were used to assess receptor phosphorylation. Cell culture experiments demonstrated that anti-proliferative effects of vandetanib resulted from inhibition of either EGFR or VEGFR-2 signalling in endothelial cells, but were associated with inhibition of EGFR signalling in tumour cells. Vandetanib inhibited both EGFR and VEGFR-2 signalling in normal lung tissue and in tumour xenografts. In a lung cancer model expressing an activating EGFR mutation, the activity of vandetanib was similar to that of a highly selective EGFR inhibitor (gefitinib), and markedly greater than that of a highly selective VEGFR inhibitor (vatalanib). These data suggest that at the plasma exposures achieved in the clinic, vandetanib will significantly inhibit both VEGFR-2 and EGFR signalling, and that both inhibition of angiogenesis and direct inhibition of tumour cell growth can contribute to treatment response.
authors.affiliation: Cancer Bioscience, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Brave
authors.forename: Rajesh
authors.initials: R
authors.lastname: Odedra
authors.forename: Neil H
authors.initials: NH
authors.lastname: James
authors.forename: Neil R
authors.initials: NR
authors.lastname: Smith
authors.forename: Gayle B
authors.initials: GB
authors.lastname: Marshall
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Acheson
authors.forename: Dawn
authors.initials: D
authors.lastname: Baker
authors.forename: Zoe
authors.initials: Z
authors.lastname: Howard
authors.forename: Lynsay
authors.initials: L
authors.lastname: Jackson
authors.forename: Kirsty
authors.initials: K
authors.lastname: Ratcliffe
authors.forename: Anna
authors.initials: A
authors.lastname: Wainwright
authors.forename: Susan C
authors.initials: SC
authors.lastname: Lovick
authors.forename: D Mark
authors.initials: DM
authors.lastname: Hickinson
authors.forename: Robert W
authors.initials: RW
authors.lastname: Wilkinson
authors.forename: Simon T
authors.initials: ST
authors.lastname: Barry
authors.forename: Georgina
authors.initials: G
authors.lastname: Speake
authors.forename: Anderson J
authors.initials: AJ
authors.lastname: Ryan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000503:physiopathology; D010641:Phenotype; D010880:Piperidines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D011799:Quinazolines; D066246:ErbB Receptors; D040301:Vascular Endothelial Growth Factor Receptor-2; C452423:vandetanib