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Antibody-based targeting of cell surface grp94 specifically inhibits cetuximab-resistant colorectal cancer growth

Title
Antibody-based targeting of cell surface grp94 specifically inhibits cetuximab-resistant colorectal cancer growth
Authors
Jeoung M.H.Kim T.-K.Kim J.W.Cho Y.B.Na H.J.Yoo B.C.Shim H.Song D.-K.Heo K.Lee S.
Ewha Authors
심현보
SCOPUS Author ID
심현보scopus
Issue Date
2019
Journal Title
Biomolecules
ISSN
2218-273XJCR Link
Citation
Biomolecules vol. 9, no. 11
Keywords
Colorectal cancerGRP94Human antibodyCetuximab resistance
Publisher
MDPI AG
Indexed
SCIE; SCOPUS scopus
Document Type
Article
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. Cetuximab, a human/mouse chimeric monoclonal antibody, is effective in a limited number of CRC patients because of cetuximab resistance. This study aimed to identify novel therapeutic targets in cetuximab-resistant CRC in order to improve clinical outcomes. Through phage display technology, we isolated a fully human antibody strongly binding to the cetuximab-resistant HCT116 cell surface and identified the target antigen as glucose-regulated protein 94 (GRP94) using proteomic analysis. Short interfering RNA-mediated GRP94 knockdown showed that GRP94 plays a key role in HCT116 cell growth. In vitro functional studies revealed that the GRP94-blocking antibody we developed strongly inhibits the growth of various cetuximab-resistant CRC cell lines. We also demonstrated that GRP94 immunoglobulin G monotherapy significantly reduces HCT116 cell growth more potently compared to cetuximab, without severe toxicity in vivo. Therefore, cell surface GRP94 might be a potential novel therapeutic target in cetuximab-resistant CRC, and antibody-based targeting of GRP94 might be an effective strategy to suppress GRP94-expressing cetuximab-resistant CRC. © 2019, MDPI AG. All rights reserved.
DOI
10.3390/biom9110681
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일반대학원 > 바이오융합과학과 > Journal papers
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