Scripps Korea Antibody Institute, Chuncheon, Gangwon 24341, Korea.
Biopharmaceutical Chemistry Major, School of Applied Chemistry, Kookmin University, Seoul 02707, Korea.
Biomolecules. 2019 Nov 1;9(11):681. doi: 10.3390/biom9110681.
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.
结直肠癌（CRC）是全球癌症死亡的主要原因之一。西妥昔单抗是一种人/鼠嵌合单克隆抗体，由于西妥昔单抗耐药性，它在有限数量的 CRC 患者中有效。本研究旨在鉴定西妥昔单抗耐药 CRC 中的新型治疗靶点，以改善临床结果。通过噬菌体展示技术，我们从西妥昔单抗耐药的 HCT116 细胞表面分离出一种与该细胞表面强烈结合的全人源抗体，并通过蛋白质组学分析鉴定靶抗原为葡萄糖调节蛋白 94（GRP94）。GRP94 短发夹 RNA 介导的敲低表明，GRP94 在 HCT116 细胞生长中发挥关键作用。体外功能研究表明，我们开发的 GRP94 阻断抗体强烈抑制各种西妥昔单抗耐药 CRC 细胞系的生长。我们还证明，与西妥昔单抗相比，GRP94 免疫球蛋白 G 单药治疗在体内更有效地减少 HCT116 细胞生长，而没有严重的毒性。因此，细胞表面 GRP94 可能是西妥昔单抗耐药 CRC 的一个潜在新型治疗靶点，针对 GRP94 的抗体靶向治疗可能是抑制表达 GRP94 的西妥昔单抗耐药 CRC 的有效策略。
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