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

Cancer Chemother Pharmacol. 2019 Apr;83(4):659-671. doi: 10.1007/s00280-019-03768-8. Epub 2019 Jan 18.


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: Biliary tract cancer; HER2; T-DM1; Trastuzumab emtansine.

MeSH terms

  • Ado-Trastuzumab Emtansine / administration & dosage*
  • Ado-Trastuzumab Emtansine / pharmacology
  • Animals
  • Antineoplastic Agents, Immunological / administration & dosage*
  • Antineoplastic Agents, Immunological / pharmacology
  • Apoptosis / drug effects
  • Biliary Tract Neoplasms / drug therapy*
  • Biliary Tract Neoplasms / genetics
  • Biliary Tract Neoplasms / pathology
  • Breast Neoplasms / drug therapy
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cholangiocarcinoma / drug therapy
  • Female
  • Humans
  • In Situ Hybridization, Fluorescence
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Targeted Therapy*
  • Receptor, ErbB-2 / genetics*
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents, Immunological
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Ado-Trastuzumab Emtansine