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ID 49553
フルテキストURL
著者
Yoshida, Ryosuke Okayama Univ, Dept Surg Gastroenterol, Grad Sch Med Dent & Pharmaceut Sci
Tazawa, Hiroshi Okayama Univ Hosp, Ctr Gene & Cell Therapy
Hashimoto, Yuuri Okayama Univ, Dept Surg Gastroenterol, Grad Sch Med Dent & Pharmaceut Sci
Yano, Shuya Okayama Univ, Dept Surg Gastroenterol, Grad Sch Med Dent & Pharmaceut Sci
Onishi, Teppei Okayama Univ, Dept Surg Gastroenterol, Grad Sch Med Dent & Pharmaceut Sci
Sasaki, Tsuyoshi Okayama Univ, Dept Orthopaed Surg, Grad Sch Med Dent & Pharmaceut Sci
Shirakawa, Yasuhiro Okayama Univ, Dept Surg Gastroenterol, Grad Sch Med Dent & Pharmaceut Sci
Kishimoto, Hiroyuki Okayama Univ, Dept Surg Gastroenterol, Grad Sch Med Dent & Pharmaceut Sci
Uno, Futoshi Okayama Univ, Dept Surg Gastroenterol, Grad Sch Med Dent & Pharmaceut Sci
Nishizaki, Masahiko Okayama Univ, Dept Surg Gastroenterol, Grad Sch Med Dent & Pharmaceut Sci
Kagawa, Shunsuke Okayama Univ, Dept Surg Gastroenterol, Grad Sch Med Dent & Pharmaceut Sci
Fujiwara, Toshiyoshi Okayama Univ, Dept Surg Gastroenterol, Grad Sch Med Dent & Pharmaceut Sci ORCID 科研費研究者番号
抄録
Trastuzumab, a humanized antibody targeting HER2, exhibits remarkable therapeutic efficacy against HER2-positive breast and gastric cancers; however, acquired resistance presents a formidable obstacle to long-term tumor responses in the majority of patients. Here, we show the mechanism of resistance to trastuzumab in HER2-positive human cancer cells and explore the molecular sensitization by exogenous expression of HER2-extracellular domain (ECD) in HER2-negative or trastuzumab-resistant human cancer cells. We found that long-term exposure to trastuzumab induced resistance in HER2-positive cancer cells; HER2 expression was downregulated, and antibody-dependent cellular cytotoxicity (ADCC) activity was impaired. We next examined the hypothesis that trastuzumab-resistant cells could be re-sensitized by the transfer of non-functional HER2-ECD. Exogenous HER2-ECD expression induced by the stable transfection of a plasmid vector or infection with a replication-deficient adenovirus vector had no apparent effect on the signaling pathway, but strongly enhanced ADCC activity in low HER2-expressing or trastuzumab-resistant human cancer cells. Our data indicate that restoration of HER2-ECD expression sensitizes HER2-negative or HER2-downregulated human cancer cells to trastuzumab-mediated ADCC, an outcome that has important implications for the treatment of human cancers.
キーワード
HER2
Extracellular domain
Trastuzumab
ADCC
Adenovirus
発行日
2012-11
出版物タイトル
Cancer Immunology, Immunotherapy
61巻
11号
開始ページ
1905
終了ページ
1916
ISSN
0340-7004
資料タイプ
学術雑誌論文
オフィシャル URL
http://dx.doi.org/10.1007/s00262-012-1249-x
関連URL
http://ousar.lib.okayama-u.ac.jp/metadata/49127
言語
English
論文のバージョン
author
査読
有り
DOI
Web of Sience KeyUT