TY - JOUR
T1 - Mechanism of resistance to trastuzumab and molecular sensitization via ADCC activation by exogenous expression of HER2-extracellular domain in human cancer cells
AU - Yoshida, Ryosuke
AU - Tazawa, Hiroshi
AU - Hashimoto, Yuuri
AU - Yano, Shuuya
AU - Onishi, Teppei
AU - Sasaki, Tsuyoshi
AU - Shirakawa, Yasuhiro
AU - Kishimoto, Hiroyuki
AU - Uno, Futoshi
AU - Nishizaki, Masahiko
AU - Kagawa, Shunsuke
AU - Fujiwara, Toshiyoshi
N1 - Funding Information:
Acknowledgments We thank Dr. Mien-Chie Hung (M.D. Anderson Cancer Center) for supplying complementary DNAs of human full-length HER2 (HER2-wt) and truncated HER2 containing extracellular and transmembrane regions (HER2-ECD). We also thank Tomoko Sueishi for her excellent technical support. This work was supported by grants-in-aid from the Ministry of Education, Science, and Culture, Japan (T. F.), and grants from the Ministry of Health and Welfare, Japan (T. F.).
PY - 2012/11
Y1 - 2012/11
N2 - Trastuzumab, a humanized antibody targeting HER2, exhibits remarkable therapeutic eYcacy against HER2-positive breast and gastric cancers; however, acquired resistance presents a formidable obstacle to longterm 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 antibodydependent 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-deWcient adenovirus vector had no apparent eVect 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.
AB - Trastuzumab, a humanized antibody targeting HER2, exhibits remarkable therapeutic eYcacy against HER2-positive breast and gastric cancers; however, acquired resistance presents a formidable obstacle to longterm 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 antibodydependent 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-deWcient adenovirus vector had no apparent eVect 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.
KW - ADCC
KW - Adenovirus
KW - Extracellular domain
KW - HER2
KW - Trastuzumab
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U2 - 10.1007/s00262-012-1249-x
DO - 10.1007/s00262-012-1249-x
M3 - Article
C2 - 22465967
AN - SCOPUS:84870985606
VL - 61
SP - 1905
EP - 1916
JO - Cancer Immunology and Immunotherapy
JF - Cancer Immunology and Immunotherapy
SN - 0340-7004
IS - 11
ER -