ヒグチ　リヨウタ   HIGUCHI Ryota   樋口　亮太    所属   医学部 医学科（附属八千代医療センター）    職種   講師
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Molecular targeting of HER2-overexpressing biliary tract cancer cells with trastuzumab emtansine, an antibody-cytotoxic drug conjugate.
掲載誌名	正式名：Cancer chemotherapy and pharmacology 略　 称：Cancer Chemother Pharmacol ISSNコード：14320843/03445704
巻・号・頁	83(4),pp.659-671
著者・共著者	Yamashita-Kashima Yoriko, Yoshimura Yasushi, Fujimura Takaaki, Shu Sei, Yanagisawa Mieko, Yorozu Keigo, Furugaki Koh, Higuchi Ryota, Shoda Junichi, Harada Naoki
発行年月	2019/04
概要	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.
DOI	10.1007/s00280-019-03768-8
PMID	30659304