PMID- 30659304
OWN - NLM
STAT- MEDLINE
DCOM- 20200120
LR  - 20200120
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Linking)
VI  - 83
IP  - 4
DP  - 2019 Apr
TI  - Molecular targeting of HER2-overexpressing biliary tract cancer cells with 
      trastuzumab emtansine, an antibody-cytotoxic drug conjugate.
PG  - 659-671
LID - 10.1007/s00280-019-03768-8 [doi]
AB  - 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.
FAU - Yamashita-Kashima, Yoriko
AU  - Yamashita-Kashima Y
AD  - Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, 
      Kamakura, Kanagawa, 247-8530, Japan.
FAU - Yoshimura, Yasushi
AU  - Yoshimura Y
AD  - Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, 
      Kamakura, Kanagawa, 247-8530, Japan.
FAU - Fujimura, Takaaki
AU  - Fujimura T
AD  - Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, 
      Kamakura, Kanagawa, 247-8530, Japan.
FAU - Shu, Sei
AU  - Shu S
AD  - Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, 
      Kamakura, Kanagawa, 247-8530, Japan.
FAU - Yanagisawa, Mieko
AU  - Yanagisawa M
AD  - Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, 
      Kamakura, Kanagawa, 247-8530, Japan.
FAU - Yorozu, Keigo
AU  - Yorozu K
AD  - Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, 
      Kamakura, Kanagawa, 247-8530, Japan.
FAU - Furugaki, Koh
AU  - Furugaki K
AD  - Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, 
      Kamakura, Kanagawa, 247-8530, Japan.
FAU - Higuchi, Ryota
AU  - Higuchi R
AD  - Department of Gastroenterological Surgery, Tokyo Women's Medical University, 8-1 
      Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.
FAU - Shoda, Junichi
AU  - Shoda J
AD  - Department of Medical Sciences, Faculty of Medicine, University of Tsukuba, 1-1-1 
      Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
FAU - Harada, Naoki
AU  - Harada N
AUID- ORCID: 0000-0003-1468-0636
AD  - Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, 
      Kamakura, Kanagawa, 247-8530, Japan. haradanok@chugai-pharm.co.jp.
LA  - eng
PT  - Journal Article
DEP - 20190118
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (Antineoplastic Agents, Immunological)
RN  - EC 2.7.10.1 (ERBB2 protein, human)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - SE2KH7T06F (Ado-Trastuzumab Emtansine)
SB  - IM
MH  - Ado-Trastuzumab Emtansine/*administration & dosage/pharmacology
MH  - Animals
MH  - Antineoplastic Agents, Immunological/*administration & dosage/pharmacology
MH  - Apoptosis/drug effects
MH  - Biliary Tract Neoplasms/*drug therapy/genetics/pathology
MH  - Breast Neoplasms/drug therapy
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cholangiocarcinoma/drug therapy
MH  - Female
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - *Molecular Targeted Therapy
MH  - Receptor, ErbB-2/*genetics
MH  - Xenograft Model Antitumor Assays
OTO - NOTNLM
OT  - Biliary tract cancer
OT  - HER2
OT  - T-DM1
OT  - Trastuzumab emtansine
EDAT- 2019/01/20 06:00
MHDA- 2020/01/21 06:00
CRDT- 2019/01/20 06:00
PHST- 2018/07/24 00:00 [received]
PHST- 2019/01/05 00:00 [accepted]
PHST- 2019/01/20 06:00 [pubmed]
PHST- 2020/01/21 06:00 [medline]
PHST- 2019/01/20 06:00 [entrez]
AID - 10.1007/s00280-019-03768-8 [pii]
AID - 10.1007/s00280-019-03768-8 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2019 Apr;83(4):659-671. doi: 
      10.1007/s00280-019-03768-8. Epub 2019 Jan 18.