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

被引:33
作者
Cunningham, Matthew P.
Thomas, Hilary
Fan, Zhen
Modjtahedi, Helmout
机构
[1] Univ Surrey, Postgrad Med Sch, Dept Oncol, Guildford GU2 7WG, Surrey, England
[2] Univ Texas, MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA
关键词
D O I
10.1158/0008-5472.CAN-06-1000
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 HCT116) 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 (IC50 = 0.52 nmol/L) and gefitinib (IC50 = 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.
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页码:7708 / 7715
页数:8
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