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