RRC ID 45226
Author Kawamoto T, Ishige K, Thomas M, Yamashita-Kashima Y, Shu S, Ishikura N, Ariizumi S, Yamamoto M, Kurosaki K, Shoda J.
Title Overexpression and gene amplification of EGFR, HER2, and HER3 in biliary tract carcinomas, and the possibility for therapy with the HER2-targeting antibody pertuzumab.
Journal J. Gastroenterol.
Abstract BACKGROUND:Pertuzumab is a humanized monoclonal antibody that binds to HER2 at an epitope that prevents HER2 from dimerizing with ligand-activated HER-family receptors. To assess the potential of pertuzumab as a new therapy, the expression status of HER family members was determined in biliary tract carcinoma (BTC), and the antitumor activity of pertuzumab was investigated by assessing the inhibition of BTC cell growth.
METHODS:The expression status of HER family members in 113 archival specimens of BTC was analyzed by using immunohistochemistry and fluorescence in situ hybridization. Using ten BTC cell lines, heregulin-alpha (HRG-α) stimulated cell proliferation and its inhibition by pertuzumab was tested in vitro. The phosphorylated HER family proteins and their respective downstream molecules were analyzed. In vivo antitumor activity of pertuzumab was evaluated in a xenograft model.
RESULTS:Protein overexpression of HER2 and/or HER3 was observed in 23-34 % of the specimens and gene amplification in 17-27 %. Seven of the ten cell lines showed HER2 and/or HER3 protein overexpression and gene amplification, and HRG-α stimulated cell proliferation was observed in four of the ten cell lines. In a BTC cell line co-overexpressing HER2 and HER3, pertuzumab potently inhibited the HRG-α stimulated cell proliferation in a dose-dependent manner, and completely blocked the phosphorylation of HER3. Suppression of downstream pathway molecules including p-AKT was also observed. Pertuzumab inhibited the in vivo growth of subcutaneous tumors, and increased the number of apoptotic cancer cells.
CONCLUSIONS:Pertuzumab exerts potent antitumor activity in BTC cells co-overexpressing HER2 and HER3. Pertuzumab provides a new therapeutic option against BTC.
Volume 50(4)
Pages 467-79
Published 2015-4
DOI 10.1007/s00535-014-0984-5
PMID 25112701
MeSH Adult Aged Aged, 80 and over Animals Antibodies, Monoclonal, Humanized / therapeutic use* Antineoplastic Agents / therapeutic use* Biliary Tract Neoplasms / drug therapy Biliary Tract Neoplasms / genetics Biliary Tract Neoplasms / metabolism* Biliary Tract Neoplasms / pathology ErbB Receptors / biosynthesis* ErbB Receptors / genetics Female Gene Amplification Gene Expression Regulation, Neoplastic / drug effects Humans Male Mice, Inbred BALB C Middle Aged Molecular Targeted Therapy / methods Neoplasm Proteins / biosynthesis Neoplasm Proteins / genetics Receptor, ErbB-2 / antagonists & inhibitors Receptor, ErbB-2 / biosynthesis Receptor, ErbB-2 / genetics Receptor, ErbB-3 / biosynthesis Receptor, ErbB-3 / genetics Trastuzumab / therapeutic use Xenograft Model Antitumor Assays
IF 5.561
Times Cited 8
WOS Category GASTROENTEROLOGY & HEPATOLOGY
Resource
Human and Animal Cells