Pertuzumab, a novel HER dimerization inhibitor, inhibits the growth of human lung cancer cells mediated by the HER3 signaling pathway

Cancer Sci. 2007 Sep;98(9):1498-503. doi: 10.1111/j.1349-7006.2007.00553.x. Epub 2007 Jul 11.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / physiology*
  • Antibodies, Monoclonal, Humanized
  • Carcinoma, Non-Small-Cell Lung / immunology
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Carcinoma, Non-Small-Cell Lung / prevention & control
  • Cell Division / physiology
  • Cell Line, Tumor
  • Cell Proliferation
  • Dimerization
  • Epidermal Growth Factor / physiology
  • ErbB Receptors / metabolism
  • Growth Inhibitors / physiology*
  • Humans
  • Ligands
  • Lung Neoplasms / immunology
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Lung Neoplasms / prevention & control
  • Neuregulin-1 / antagonists & inhibitors
  • Neuregulin-1 / physiology
  • Phosphorylation
  • Receptor, ErbB-3 / antagonists & inhibitors*
  • Receptor, ErbB-3 / metabolism
  • Receptor, ErbB-3 / physiology*
  • Signal Transduction / immunology
  • Signal Transduction / physiology*


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Growth Inhibitors
  • Ligands
  • Neuregulin-1
  • heregulin alpha
  • Epidermal Growth Factor
  • ErbB Receptors
  • Receptor, ErbB-3
  • pertuzumab