Antibody-based targeting of cell surface grp94 specifically inhibits cetuximab-resistant colorectal cancer growth
- 주제(키워드) Cetuximab resistance , Colorectal cancer , GRP94 , Human antibody
- 등재 SCIE, SCOPUS
- OA유형 Green Published, gold
- 발행기관 MDPI AG
- 발행년도 2019
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000162459
- 본문언어 영어
- Published As http://dx.doi.org/10.3390/biom9110681
- PubMed https://pubmed.ncbi.nlm.nih.gov/31683810
초록/요약
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.
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