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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

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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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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Acknowledgments

This study was supported by Grants-in-Aid (Nos. 15590618, 23390318, and 24390323) for scientific research from the Ministry of Education, Culture, Sports, Science and Technology in Japan.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, Tokyo, Japan

    Toru Kawamoto, Shunichi Ariizumi & Masakazu Yamamoto

  2. Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan

    Kazunori Ishige

  3. Department of Gastrointestinal Medical Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA

    Melanie Thomas

  4. Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kanagawa, Japan

    Yoriko Yamashita-Kashima, Sei Shu & Nobuyuki Ishikura

  5. Department of Legal Medicine, School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan

    Kunihiko Kurosaki

  6. Department of Medical Science, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan

    Junichi Shoda

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  1. Toru Kawamoto
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Correspondence to Junichi Shoda.

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Kawamoto, T., Ishige, K., Thomas, M. et al. Overexpression and gene amplification of EGFR, HER2, and HER3 in biliary tract carcinomas, and the possibility for therapy with the HER2-targeting antibody pertuzumab. J Gastroenterol 50, 467–479 (2015). https://doi.org/10.1007/s00535-014-0984-5

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  • DOI: https://doi.org/10.1007/s00535-014-0984-5

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