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ID 49553
FullText URL
Author
Yoshida, Ryosuke
Tazawa, Hiroshi ORCID Kakenhi
Hashimoto, Yuuri
Yano, Shuya
Onishi, Teppei
Sasaki, Tsuyoshi
Uno, Futoshi
Kagawa, Shunsuke ORCID Kakenhi
Fujiwara, Toshiyoshi ORCID Kakenhi
Abstract
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.
Keywords
HER2
Extracellular domain
Trastuzumab
ADCC
Adenovirus
Published Date
2012-11
Publication Title
Cancer Immunology, Immunotherapy
Volume
volume61
Issue
issue11
Start Page
1905
End Page
1916
ISSN
0340-7004
Content Type
Journal Article
Official Url
http://dx.doi.org/10.1007/s00262-012-1249-x
Related Url
http://ousar.lib.okayama-u.ac.jp/metadata/49127
language
英語
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author
Refereed
True
DOI
Web of Sience KeyUT