Mechanism of resistance to trastuzumab and molecular sensitization via ADCC activation by exogenous expression of HER2-extracellular domain in human cancer cells

• Published in: Cancer Immunology, Immunotherapy Vol. 61; no. 11; pp. 1905 - 1916
• Main Authors: Yoshida, Ryosuke, Tazawa, Hiroshi, Hashimoto, Yuuri, Yano, Shuya, Onishi, Teppei, Sasaki, Tsuyoshi, Shirakawa, Yasuhiro, Kishimoto, Hiroyuki, Uno, Futoshi, Nishizaki, Masahiko, Kagawa, Shunsuke, Fujiwara, Toshiyoshi
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.11.2012; Springer; Springer Nature B.V
• Subjects: Adenocarcinoma - drug therapy; Adenovirus; Adenoviruses; Antibodies; Antibodies, Monoclonal, Humanized - therapeutic use; Antibody-Dependent Cell Cytotoxicity; Antibody-dependent cell-mediated cytotoxicity; Antigens; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Breast cancer; Breast Neoplasms - drug therapy; Cancer Research; Cancer therapies; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemotherapy; Cytotoxicity; Data processing; Dentistry; Drug Resistance, Neoplasm; Epidermal growth factor; ErbB-2 protein; Expression vectors; Female; Gastric cancer; Humans; Immunology; Immunotherapy; Infection; Kinases; Medical sciences; Medicine; Medicine & Public Health; Oncology; Original; Original Article; Pharmaceutical sciences; Pharmacology. Drug treatments; Plasmids; Receptor, ErbB-2 - biosynthesis; Signal transduction; Stomach Neoplasms - drug therapy; Transfection; Trastuzumab; Tumors; Japan; HER2; Adenovirus; ADCC; Extracellular domain; Trastuzumab; Antineoplastic agent; Adenoviridae; erbB2 Gene; Activation; Monoclonal antibody; Regulation(control); Immunotherapy; Sensitization; Mechanism of action; Tumor cell; Protooncogene; Human; Exogenous; Gene expression; Extracellular; Human Epidermal growth factor Receptor 2; Virus; Resistance; Treatment; C-Onc gene; Antibody-dependent cell cytotoxicity; Gene therapy
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-012-1249-x

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.