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

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

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish
Article number681
JournalBiomolecules
Volume9
Issue number11
DOIs
StatePublished - Nov 2019

Keywords

  • Cetuximab resistance
  • Colorectal cancer
  • GRP94
  • Human antibody

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