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

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.
Authors	Mee Hyun Jeoung, Taek-Keun Kim, Ji Woong Kim, Yea Bin Cho, Hee Jun Na, Byong Chul Yoo, Hyunbo Shim, Dong-Keun Song, Kyun Heo, Sukmook Lee
Journal	Biomolecules (Biomolecules) Vol. 9 Issue 11 (11 01 2019) ISSN: 2218-273X [Electronic] Switzerland
PMID	31683810 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antibodies, Monoclonal, Humanized Antineoplastic Agents, Immunological HSP70 Heat-Shock Proteins Membrane Proteins glucose-regulated proteins Cetuximab
Topics	Animals Antibodies, Monoclonal, Humanized (administration & dosage) Antineoplastic Agents, Immunological (administration & dosage) Cell Proliferation (drug effects) Cetuximab (administration & dosage) Colorectal Neoplasms (drug therapy, genetics, immunology, physiopathology) Drug Resistance, Neoplasm HCT116 Cells HSP70 Heat-Shock Proteins (genetics, immunology) Humans Membrane Proteins (genetics, immunology) Mice Mice, Inbred BALB C

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