• Open Access

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

Authors


To whom correspondence should be addressed. E-mail: knishio@med.kindai.ac.jp

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)-α. Pertuzumab significantly inhibited the HRG-α-stimulated cellular growth of the 11_18 cells. Pertuzumab blocked HRG-α-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-α-stimulated HER2/HER3 heterodimer formation. HRG-α-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-α nor inhibited by pertuzumab. The present results suggest that pertuzumab is effective against HRG-α-dependent cell growth in lung cancer cells through inhibition of HRG-α-stimulated HER2/HER3 signaling. (Cancer Sci 2007; 98: 1498–1503)

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