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Promising Therapeutic Efficacy of GC1118, an Anti-EGFR Antibody, against KRAS Mutation-Driven Colorectal Cancer Patient-Derived Xenografts
- Source :
- International Journal of Molecular Sciences, Volume 20, Issue 23
- Publication Year :
- 2019
-
Abstract
- 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.
- Subjects :
- Colorectal cancer
Cetuximab
medicine.disease_cause
KRAS mutation
Mice
Phosphatidylinositol 3-Kinases
PI3K/mTOR/AKT inhibitor
Tumor Cells, Cultured
Epidermal growth factor receptor
Spectroscopy
biology
TOR Serine-Threonine Kinases
General Medicine
EGFR-targeting therapeutic antibody
Computer Science Applications
ErbB Receptors
Female
KRAS
Colorectal Neoplasms
medicine.drug
Signal Transduction
patient-derived xenograft
Transplantation, Heterologous
Mice, Nude
colorectal cancer
Antibodies, Monoclonal, Humanized
Catalysis
Article
Inorganic Chemistry
Proto-Oncogene Proteins p21(ras)
medicine
Panitumumab
Animals
Humans
Physical and Theoretical Chemistry
Autocrine signalling
Molecular Biology
Protein kinase B
neoplasms
Protein Kinase Inhibitors
PI3K/AKT/mTOR pathway
business.industry
Organic Chemistry
medicine.disease
digestive system diseases
Mutation
Cancer research
biology.protein
business
Proto-Oncogene Proteins c-akt
Subjects
Details
- ISSN :
- 14220067
- Volume :
- 20
- Issue :
- 23
- Database :
- OpenAIRE
- Journal :
- International journal of molecular sciences
- Accession number :
- edsair.doi.dedup.....3ad9e7fdaadf0a4c10812d07b086f36c