Cited by 169HER2/EGFR in Cancer ResearchRNA Interference and Gene DeliveryAdvanced biosensing and bioanalysis techniques

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

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Mahlknecht, Georg, Maron, Ruth, Mancini, Maicol, Schechter, Bilha, Sela, Michael, Yarden, Yosef·2013·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1302594110PMC PMC3657787

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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.

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Authors: Mahlknecht, G., Maron, R., Mancini, M., Schechter, B., Sela, M., & Yarden, Y.
Affiliations: Weizmann Institute of Science (IL)
Departments of aImmunology and
ORCID: Mancini, Maicol
Yarden, Yosef
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2013-04-29
Volume: 110
Issue: 20
Pages: 8170-8175
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.1302594110
PMC: PMC3657787
OpenAlex: W2062141406
Cited by: 169
References: 26
Citations by year: 2026: 11 · 2025: 16 · 2024: 14 · 2023: 10 · 2022: 16 · 2021: 13 · 2020: 15 · 2019: 14 · 2018: 16 · 2017: 10 · 2016: 8 · 2015: 12 · 2014: 13 · 2013: 1
FWCI: 6.07
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Cancer Institute (CA072981, R01CA072981, R37CA072981)
Topics: Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Advanced biosensing and bioanalysis techniques
Keywords: DNA aptamers, gastric cancer, lysosomal degradation, receptor tyrosine kinase, endocytosis, tumor growth inhibition, cell surface translocation, aptamer therapeutics
MeSH terms: Animals, Antineoplastic Agents, Cross-Linking Reagents, Cytoplasm, DNA, Female, Humans, Lysosomes, Mice, Nude, Neoplasm Transplantation, Nucleotides, Protein Binding, Stomach Neoplasms, Receptor, ErbB-2, Erb-b2 Receptor Tyrosine Kinases, Cell Line, Tumor, Cell Proliferation, Mice, Aptamers, Nucleotide

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

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