Abstract
The epidermal growth factor receptor (EGFR) is often aberrantly expressed in colorectal cancer, and several EGFR inhibitors have been approved for the treatment of cancer patients. However, the expression levels and prognostic significance of the EGFR reported for colorectal cancer varies between studies, and there has been no clear association between EGFR expression and response to the EGFR inhibitors. The aim of the present study was therefore to investigate the expression of the EGFR, HER-2, and IGF-IR in a panel of human colorectal tumour cell lines and their association with response to the EGFR and/or IGF-IR inhibitors. The expression pattern and clinical significance of the EGFR, EGFRvIII, phosphorylated EGFR, HER-2 and IGF-IR was also determined in the tumour specimens from 87 Dukes’ C colorectal cancer patients. Overexpression of the EGFR, HER-2 and IGF-IR was found to be uncommon in 12 human colorectal tumour cell lines. Of these, only DiFi cells overexpressed the EGFR, contained constitutively active EGFR and were highly sensitive to growth inhibition by anti-EGFR mAh ICR62 and the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. While the anti-EGFR mAh and EGFR TKIs were found to have overlapping, but not identical modes of action, co-targeting the EGFR ligand binding domain and tyrosine kinase domain with a combination of mAb and TKI was not superior over targeting tumour cells with the single-agent in-vitro. In contrast, treatment with a combination of the EGFR inhibitors and an IGF-IR TKI was more effective than treatment with the single-agent. Using three different anti-EGFR antibodies, >76% of 87 Dukes’ C colorectal cancer cases were found to be EGFR positive. Interestingly, 34% and 8% of the cases were also EGFRvIII and pEGFR positive, respectively. In addition, IGF-IR, EGFR, and HER-2 coexpression was found to be common (>62 %) in the 87 Dukes’ C patients. While EGFR, EGFRvIII, and HER-2 expression were predominantly cytoplasmic, 60% of patients were found to express membranous IGF-IR. While no significant associations were found between patient survival and growth factor receptor expression, cytoplasmic expression of the EGFRvIII and coexpression of the IGF-IR, EGFR, and HER-2 was associated with improved response to radiotherapy. Since there has been no clear association between EGFR expression and response to the EGFR inhibitors in clinical studies, the expression of IGF-IR has been associated with resistance to EGFR and HER-2 inhibitors in the experimental setting, and coexpression of the EGFR, EGFRvIII, IGF-IR and HER-2 was found to be common in colorectal cancer patients, these results provide a rationale for investigating the therapeutic benefit of co-targeting the IGF-IR, EGFR, and HER-2 in colorectal cancer patients and their potential as predictive factors for response to therapy with the EGFR inhibitors.