Promising Therapeutic Efficacy of GC1118, an Anti-EGFR Antibody, against KRAS Mutation-Driven Colorectal Cancer Patient-Derived Xenografts
Open accessAbstract
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.
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GC1118 displays inhibitory effects against patient-derived xenografts from colorectal cancer tumours with a KRAS mutation, especially those with elevated expression of high-affinity ligands.
“In addition, GC1118 is a novel, fully humanized anti-EGFR IgG1 antibody that displays inhibitory effects against patient-derived xenografts from CRC tumours with a KRAS mutation [40], especially in those with elevated expression of high-affinity ligands [72].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [40]
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Personalized treatment for advanced colorectal cancer: KRAS and beyond
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Self-citationSimultaneous targeting of EGFR and mTOR inhibits the growth of colorectal carcinoma cells
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Zhou, J., Ji, Q., & Li, Q. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02130-2 · Cited by 246 · see citing works
Recent Updates on the Significance of KRAS Mutations in Colorectal Cancer Biology
László, L., Kurilla, A., Takács, T., Kudlik, G., Koprivanacz, K., Buday, L., & Vas, V. (2021) · Cells · doi:10.3390/cells10030667 · Cited by 58 · see citing works
- Authors
- Lee, H., Son, E., Lee, K., Lee, Y., Kim, Y., Lee, J.-C., Lim, Y., Hur, M., Kim, D., & Nam, D.-H.
- Affiliations
- Sungkyunkwan University (KR)
- Samsung Medical Center (KR)
- Mogam Institute for Biomedical Research (KR)
- Corresponding author
- Kim, Donggeon
- Nam, Do-Hyun
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2019-11-24
- Volume
- 20
- Issue
- 23
- Pages
- 5894
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC6928876
- OpenAlex
- W2989577472
- Cited by
- 22
- References
- 91
- Citations by year
- 2026: 2 · 2025: 3 · 2023: 6 · 2022: 1 · 2021: 8 · 2020: 2
- FWCI
- 1.15
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- The Bio & Medical Technology Development Program of the National Research Foundation (NRF), funded by the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Republic of Korea (NRF-2017R1A2B4011780)
- The Korean government (MSIP) (NRF-2016R1A5A2945889)
- The Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C3418)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Keywords
- anti-EGFR monoclonal antibody, KRAS mutation, metastatic colorectal cancer, patient-derived xenografts, PI3K/Akt signaling, BEZ235, cetuximab, combination therapy, drug resistance
- MeSH terms
- Cetuximab, Animals, Female, Humans, Mice, Nude, Mutation, Transplantation, Heterologous, Tumor Cells, Cultured, Colorectal Neoplasms, Signal Transduction, Proto-Oncogene Proteins p21(ras), Phosphatidylinositol 3-Kinases, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Mice, TOR Serine-Threonine Kinases, Antibodies, Monoclonal, Humanized, ErbB Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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