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Molecular targeting of HER2-overexpressing biliary tract cancer cells with trastuzumab emtansine, an antibody–cytotoxic drug conjugate

  • Yoriko Yamashita-Kashima
  • Yasushi Yoshimura
  • Takaaki Fujimura
  • Sei Shu
  • Mieko Yanagisawa
  • Keigo Yorozu
  • Koh Furugaki
  • Ryota Higuchi
  • Junichi Shoda
  • Naoki HaradaEmail author
Original Article
  • 115 Downloads

Abstract

Purpose

Trastuzumab emtansine (T-DM1) provides clinical benefit in breast cancers overexpressing human epidermal growth factor receptor 2 (HER2). However, its efficacy against biliary tract cancers (BTC) has not been evaluated. In this study, the effectiveness of T-DM1 in various BTC cell lines and xenograft models with different levels of HER2 expression was investigated.

Methods

HER2 expression status in xenografts and patient tissue microarrays was assessed by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH). Cell-surface HER2 expression levels and cell growth inhibition in response to T-DM1 were examined in 17 BTC cell lines. The antitumor activity of T-DM1 was evaluated in four xenograft mouse models with different levels of HER2 expression. The effects of T-DM1 on HER2 signaling, antibody-dependent cell-mediated cytotoxicity (ADCC), cell cycle, and apoptosis were assessed in vitro.

Results

Cell-surface expression of HER2 was observed in both gallbladder carcinoma and cholangiocarcinoma tissues. The anti-proliferative activity of T-DM1 was higher in BTC cell lines and breast cancer cell lines with higher levels of HER2 expression. The HER2 status (IHC score|HER2-to-CEP17 ratio by FISH testing) of each BTC xenograft was 3 +|8.3 for KMCH-1, 2 +|4.7 for Mz-ChA-1, 1 +/0|1.4 for OCUG-1, and 0|1.1 for KKU-100, and T-DM1 showed antitumor activity in proportion to the HER2 status. T-DM1 inhibited HER2 signaling and induced ADCC, mitotic arrest, and apoptosis in KMCH-1 cells.

Conclusions

T-DM1 exhibited preclinical activity in HER2-overexpressing BTC. Further evaluation in clinical studies is warranted.

Keywords

T-DM1 Trastuzumab emtansine HER2 Biliary tract cancer 

Notes

Acknowledgements

We thank Marie Mochizuki and Mirei Kouno (Product Research Department, Chugai Pharmaceutical Co., Ltd.) for technical assistance; Dr. Kaori Fujimoto-Ouchi (Product Research Department, Chugai Pharmaceutical Co., Ltd.) for helpful suggestions and comments about this study; and Dr. Banchob Spira (Khon Kaen University) for kindly providing KKU-100, KKU-055 and KKU-0213 cell lines.

Compliance with ethical standards

Conflict of interest

Junichi Shoda received research fee and grants from Chugai Pharmaceutical Co., Ltd. and other authors have no conflict of interest.

Ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee at Chugai Pharmaceuticals, Co., Ltd. and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The human tissues were processed anonymously inhibiting the revelation of the donor’s identity.

Supplementary material

280_2019_3768_MOESM1_ESM.docx (21 kb)
Supplementary material 1 (DOCX 21 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Yoriko Yamashita-Kashima
    • 1
  • Yasushi Yoshimura
    • 1
  • Takaaki Fujimura
    • 1
  • Sei Shu
    • 1
  • Mieko Yanagisawa
    • 1
  • Keigo Yorozu
    • 1
  • Koh Furugaki
    • 1
  • Ryota Higuchi
    • 2
  • Junichi Shoda
    • 3
  • Naoki Harada
    • 1
    Email author
  1. 1.Product Research DepartmentChugai Pharmaceutical Co., Ltd.KamakuraJapan
  2. 2.Department of Gastroenterological SurgeryTokyo Women’s Medical UniversityTokyoJapan
  3. 3.Department of Medical Sciences, Faculty of MedicineUniversity of TsukubaTsukubaJapan

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