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01.04.2015 | Original Article—Liver, Pancreas, and Biliary Tract

Overexpression and gene amplification of EGFR, HER2, and HER3 in biliary tract carcinomas, and the possibility for therapy with the HER2-targeting antibody pertuzumab

verfasst von: Toru Kawamoto, Kazunori Ishige, Melanie Thomas, Yoriko Yamashita-Kashima, Sei Shu, Nobuyuki Ishikura, Shunichi Ariizumi, Masakazu Yamamoto, Kunihiko Kurosaki, Junichi Shoda

Erschienen in: Journal of Gastroenterology | Ausgabe 4/2015

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Abstract

Background

Pertuzumab is a humanized monoclonal antibody that binds to HER2 at an epitope that prevents HER2 from dimerizing with ligand-activated HER-family receptors. To assess the potential of pertuzumab as a new therapy, the expression status of HER family members was determined in biliary tract carcinoma (BTC), and the antitumor activity of pertuzumab was investigated by assessing the inhibition of BTC cell growth.

Methods

The expression status of HER family members in 113 archival specimens of BTC was analyzed by using immunohistochemistry and fluorescence in situ hybridization. Using ten BTC cell lines, heregulin-alpha (HRG-α) stimulated cell proliferation and its inhibition by pertuzumab was tested in vitro. The phosphorylated HER family proteins and their respective downstream molecules were analyzed. In vivo antitumor activity of pertuzumab was evaluated in a xenograft model.

Results

Protein overexpression of HER2 and/or HER3 was observed in 23–34 % of the specimens and gene amplification in 17–27 %. Seven of the ten cell lines showed HER2 and/or HER3 protein overexpression and gene amplification, and HRG-α stimulated cell proliferation was observed in four of the ten cell lines. In a BTC cell line co-overexpressing HER2 and HER3, pertuzumab potently inhibited the HRG-α stimulated cell proliferation in a dose-dependent manner, and completely blocked the phosphorylation of HER3. Suppression of downstream pathway molecules including p-AKT was also observed. Pertuzumab inhibited the in vivo growth of subcutaneous tumors, and increased the number of apoptotic cancer cells.

Conclusions

Pertuzumab exerts potent antitumor activity in BTC cells co-overexpressing HER2 and HER3. Pertuzumab provides a new therapeutic option against BTC.

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Titel: Overexpression and gene amplification of EGFR, HER2, and HER3 in biliary tract carcinomas, and the possibility for therapy with the HER2-targeting antibody pertuzumab
verfasst von: Toru Kawamoto
Kazunori Ishige
Melanie Thomas
Yoriko Yamashita-Kashima
Sei Shu
Nobuyuki Ishikura
Shunichi Ariizumi
Masakazu Yamamoto
Kunihiko Kurosaki
Junichi Shoda
Publikationsdatum: 01.04.2015
Verlag: Springer Japan
Erschienen in: Journal of Gastroenterology / Ausgabe 4/2015
Print ISSN: 0944-1174
Elektronische ISSN: 1435-5922
DOI: https://doi.org/10.1007/s00535-014-0984-5

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Overexpression and gene amplification of EGFR, HER2, and HER3 in biliary tract carcinomas, and the possibility for therapy with the HER2-targeting antibody pertuzumab