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The HER2 S310F Mutant Can Form an Active Heterodimer with the EGFR, Which Can Be Inhibited by Cetuximab but Not by Trastuzumab as well as Pertuzumab
Open AccessArticle

Antibody-Based Targeting of Cell Surface GRP94 Specifically Inhibits Cetuximab-Resistant Colorectal Cancer Growth

Scripps Korea Antibody Institute, Chuncheon, Gangwon 24341, Korea
Biopharmaceutical Chemistry Major, School of Applied Chemistry, Kookmin University, Seoul 02707, Korea
Research Institute, National Cancer Center, Goyang, Gyeonggi 10408, Korea
Department of Bioinspired Science and Life Science, Ewha Womans University, Seoul 03760, Korea
Department of Pharmacology, College of Medicine, Hallym University, Chuncheon, Gangwon 24252, Korea
Author to whom correspondence should be addressed.
Biomolecules 2019, 9(11), 681;
Received: 10 September 2019 / Revised: 21 October 2019 / Accepted: 27 October 2019 / Published: 1 November 2019
(This article belongs to the Special Issue Advances in Antibody Therapy of Cancer)
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. View Full-Text
Keywords: cetuximab resistance; GRP94; human antibody; colorectal cancer cetuximab resistance; GRP94; human antibody; colorectal cancer
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MDPI and ACS Style

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. Antibody-Based Targeting of Cell Surface GRP94 Specifically Inhibits Cetuximab-Resistant Colorectal Cancer Growth. Biomolecules 2019, 9, 681.

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