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Aptamer to ErbB-2/HER2 enhances degradation of the target and inhibits tumorigenic growth

Author:
Mahlknecht, Georg, Maron, Ruth, Mancini, Maicol, Schechter, Bilha, Sela, Michael, Yarden, Yosef
Source:
Proceedings of the National Academy of Sciences of the United States of America 2013 v.110 no.20 pp. 8170-8175
ISSN:
0027-8424
Subject:
DNA, DNA libraries, antineoplastic activity, cell growth, erbB-2 receptor, gene overexpression, humans, monoclonal antibodies, neoplasm cells, oligonucleotides, oncogene proteins, stomach neoplasms, surface proteins
Abstract:
Aptamers, oligonucleotides able to avidly bind cellular targets, are emerging as promising therapeutic agents, analogous to monoclonal antibodies. We selected from a DNA library an aptamer specifically recognizing human epidermal growth factor receptor 2 (ErbB-2/HER2), a receptor tyrosine kinase, which is overexpressed in a variety of human cancers, including breast and gastric tumors. Treatment of human gastric cancer cells with a trimeric version (42 nucleotides) of the selected aptamer (14 nucleotides) resulted in reduced cell growth in vitro, but a monomeric version was ineffective. Likewise, when treated with the trimeric aptamer, animals bearing tumor xenografts of human gastric origin reflected reduced rates of tumor growth. The antitumor effect of the aptamer was nearly twofold stronger than that of a monoclonal anti–ErbB-2/HER2 antibody. Consistent with aptamer-induced intracellular degradation of ErbB-2/HER2, incubation of gastric cancer cells with the trimeric aptamer promoted translocation of ErbB-2/HER2 from the cell surface to cytoplasmic puncta. This translocation was associated with a lysosomal hydrolase-dependent clearance of the ErbB-2/HER2 protein from cell extracts. We conclude that targeting ErbB-2/HER2 with DNA aptamers might retard the tumorigenic growth of gastric cancer by means of accelerating lysosomal degradation of the oncoprotein. This work exemplifies the potential pharmacological utility of aptamers directed at cell surface proteins, and it highlights an endocytosis-mediated mechanism of tumor inhibition.
Agid:
1736733