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Promising Therapeutic Efficacy of GC1118, an Anti-EGFR Antibody, against KRAS Mutation-Driven Colorectal Cancer Patient-Derived Xenografts

by Hye Won Lee 1,2,†, Eunju Son 3,†, Kyoungmin Lee 3,4,†, Yeri Lee 3,5, Yejin Kim 3,4, Jae-Chul Lee 6, Yangmi Lim 6, Minkyu Hur 6, Donggeon Kim 3,5,* and Do-Hyun Nam 3,4,7,*
1
Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16149, Korea
2
Single Cell Network Research Center, Sungkyunkwan University, Suwon 16149, Korea
3
Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, Korea
4
Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul 06351, Korea
5
Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Korea
6
Translational Research 1 Team, MOGAM Institute for Biomedical Research, Yongin 16924, Korea
7
Department of Neurosurgery, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul 06531, Korea
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(23), 5894; https://doi.org/10.3390/ijms20235894
Received: 9 November 2019 / Accepted: 22 November 2019 / Published: 24 November 2019
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
Epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies, including cetuximab and panitumumab, are used to treat metastatic colorectal cancer (mCRC). However, this treatment is only effective for a small subset of mCRC patients positive for the wild-type KRAS GTPase. GC1118 is a novel, fully humanized anti-EGFR IgG1 antibody that displays potent inhibitory effects on high-affinity EGFR ligand-induced signaling and enhanced antibody-mediated cytotoxicity. In this study, using 51 CRC patient-derived xenografts (PDXs), we showed that KRAS mutants expressed remarkably elevated autocrine levels of high-affinity EGFR ligands compared with wild-type KRAS. In three KRAS-mutant CRCPDXs, GC1118 was more effective than cetuximab, whereas the two agents demonstrated comparable efficacy against three wild-type KRAS PDXs. Persistent phosphatidylinositol-3-kinase (PI3K)/AKT signaling was thought to underlie resistance to GC1118. In support of these findings, a preliminary improved anti-cancer response was observed in a CRC PDX harboring mutated KRAS with intrinsically high AKT activity using GC1118 combined with the dual PI3K/mammalian target of rapamycin (mTOR)/AKT inhibitor BEZ-235, without observed toxicity. Taken together, the superior antitumor efficacy of GC1118 alone or in combination with PI3K/mTOR/AKT inhibitors shows great therapeutic potential for the treatment of KRAS-mutant mCRC with elevated ratios of high- to low-affinity EGFR ligands and PI3K-AKT pathway activation. View Full-Text
Keywords: colorectal cancer; patient-derived xenograft; EGFR-targeting therapeutic antibody; KRAS mutation; PI3K/mTOR/AKT inhibitor colorectal cancer; patient-derived xenograft; EGFR-targeting therapeutic antibody; KRAS mutation; PI3K/mTOR/AKT inhibitor
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Lee, H.W.; Son, E.; Lee, K.; Lee, Y.; Kim, Y.; Lee, J.-C.; Lim, Y.; Hur, M.; Kim, D.; Nam, D.-H. Promising Therapeutic Efficacy of GC1118, an Anti-EGFR Antibody, against KRAS Mutation-Driven Colorectal Cancer Patient-Derived Xenografts. Int. J. Mol. Sci. 2019, 20, 5894.

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