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18.01.2019 | Original Article

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

verfasst von: Yoriko Yamashita-Kashima, Yasushi Yoshimura, Takaaki Fujimura, Sei Shu, Mieko Yanagisawa, Keigo Yorozu, Koh Furugaki, Ryota Higuchi, Junichi Shoda, Naoki Harada

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 4/2019

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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.

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Titel: Molecular targeting of HER2-overexpressing biliary tract cancer cells with trastuzumab emtansine, an antibody–cytotoxic drug conjugate
verfasst von: Yoriko Yamashita-Kashima
Yasushi Yoshimura
Takaaki Fujimura
Sei Shu
Mieko Yanagisawa
Keigo Yorozu
Koh Furugaki
Ryota Higuchi
Junichi Shoda
Naoki Harada
Publikationsdatum: 18.01.2019
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 4/2019
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-019-03768-8

Springer Medizin

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