title: Pertuzumab, a novel HER dimerization inhibitor, inhibits the growth of human lung cancer cells mediated by the HER3 signaling pathway.
abstract: A humanized anti-HER2 monoclonal antibody pertuzumab (Omnitarg, 2C4), binding to a different HER2 epitope than trastuzumab, is known as an inhibitor of heterodimerization of the HER receptors. Potent antitumor activity against HER2-expressing breast and prostate cancer cell lines has been clarified, but this potential is not clear against lung cancers. The authors investigated the in vitro anti-tumor activity of pertuzumab against eight non-small cell lung cancer cells expressing various members of the HER receptors. A lung cancer 11_18 cell line expressed a large amount of HER2 and HER3, and its cell growth was stimulated by an HER3 ligand, heregulin (HRG)-alpha. Pertuzumab significantly inhibited the HRG-alpha-stimulated cellular growth of the 11_18 cells. Pertuzumab blocked HRG-alpha-stimulated phosphorylation of HER3, mitogen-activated protein kinase (MAPK), and Akt. In contrast, pertuzumab failed to block epidermal growth factor (EGF)-stimulated phosphorylation of EGF receptor (EGFR) and MAPK. Immunoprecipitation showed that pertuzumab inhibited HRG-alpha-stimulated HER2/HER3 heterodimer formation. HRG-alpha-stimulated HER3 phosphorylation was also observed in the PC-9 cells co-overexpressing EGFR, HER2, and HER3, but the cell growth was neither stimulated by HRG-alpha nor inhibited by pertuzumab. The present results suggest that pertuzumab is effective against HRG-alpha-dependent cell growth in lung cancer cells through inhibition of HRG-alpha-stimulated HER2/HER3 signaling.
authors.affiliation: Shien-Laboratory, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Sakai
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yokote
authors.forename: Kimiko
authors.initials: K
authors.lastname: Murakami-Murofushi
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Saijo
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
mesh_terms: D000911:Antibodies, Monoclonal / Q000502:physiology*; D061067:Antibodies, Monoclonal, Humanized; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019281:Dimerization; D004815:Epidermal Growth Factor / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism; D006131:Growth Inhibitors / Q000502:physiology*; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D020890:Neuregulin-1 / Q000037:antagonists & inhibitors / Q000502:physiology; D010766:Phosphorylation; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D006131:Growth Inhibitors; D008024:Ligands; D020890:Neuregulin-1; C117463:heregulin alpha; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020893:Receptor, ErbB-3; C485206:pertuzumab