Responses of human colorectal tumor cells to treatment with the anti-epidermal growth factor receptor monoclonal antibody ICR62 used alone and in combination with the EGFR tyrosine kinase inhibitor gefitinib

The anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab has been approved for the treatment of patients with metastatic colorectal cancer. However, there is currently no reliable marker for response to therapy with the EGFR inhibitors. In this study, we investigated the sensit...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2006-08, Vol.66 (15), p.7708-7715
Main Authors: CUNNINGHAM, Matthew P, THOMAS, Hilary, ZHEN FAN, MODJTAHEDI, Helmout
Format: Article
Language:English
Subjects:
Antibodies, Monoclonal - pharmacology
Antineoplastic agents
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Biological and medical sciences
Cell Growth Processes - drug effects
Cell Line, Tumor
Colorectal Neoplasms - drug therapy
Colorectal Neoplasms - enzymology
Colorectal Neoplasms - therapy
Humans
Medical sciences
Mitogen-Activated Protein Kinases - metabolism
Pharmacology. Drug treatments
Phosphorylation
Proto-Oncogene Proteins c-akt - metabolism
Quinazolines - pharmacology
Receptor, Epidermal Growth Factor - antagonists & inhibitors
Receptor, Epidermal Growth Factor - biosynthesis
Receptor, Epidermal Growth Factor - immunology
Receptor, Epidermal Growth Factor - metabolism
Receptor, ErbB-2 - biosynthesis
Tumors
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Summary:The anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab has been approved for the treatment of patients with metastatic colorectal cancer. However, there is currently no reliable marker for response to therapy with the EGFR inhibitors. In this study, we investigated the sensitivity of 10 human colorectal tumor cell lines (DiFi, CCL218, CCL221, CCL225, CCL227, CCL228, CCL231, CCL235, CCL244, and HCT-116) to treatment with our anti-EGFR monoclonal antibody, ICR62, and/or the EGFR tyrosine kinase inhibitor, gefitinib. Of the cells examined, only DiFi contained high levels of constitutively active EGFR and were highly sensitive to treatment with both ICR62 (IC(50) = 0.52 nmol/L) and gefitinib (IC(50) = 27.5 nmol/L). In contrast, the growth of other tumor cell lines, which contained low levels of the EGFR, HER-2, and pAkt but comparable or even higher basal levels of phosphorylated mitogen-activated protein kinase (pMAPK), were relatively resistant to treatment with both inhibitors. Both ICR62 and gefitinib induced EGFR down-regulation, reduced the basal levels of pEGFR at five known tyrosine residues, pMAPK, and pAkt, and increased the sub-G(1) population in DiFi cells. However, treatment with a combination of ICR62 and gefitinib neither sensitized colorectal tumor cells that were insensitive to treatment with the single agent nor enhanced the growth-inhibitory effect of the single agent in DiFi cells. These results indicate that basal levels of pMAPK and pAkt are not good indicators of response to the EGFR inhibitors in colorectal cancer cells and dual targeting of the EGFR by a combination of ICR62 and gefitinib is not superior to treatment with a single agent.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-06-1000