Dual-agent molecular targeting of growth factor receptors in hepatocellular cancer: Combining anti-EGFR antibody with an EGFR tyrosine kinase inhibitor

Abstract

Aims: Hepatocellular carcinoma (HCC) is one of the most common cancer-related causes of death worldwide. In light of the very poor 5-year-survival new therapeutic approaches are mandatory. Recently, evidence has been accumulated that the epidermal growth factor receptor (EGFR) is a promising target for cancer therapy. Several reports indicate that EGFR is expressed frequently in HCC, most likely contributing to the aggressive growth characteristics of these tumors. Cetuximab, a chimeric monoclonal IgG1 antibody directed against the EGFR, potently suppresses the growth of various cancers but its effect on HCC remains to be explored. We therefore studied the antineoplastic potency of cetuximab in human HCC cells. Results: Cetuximab inhibited growth of p53 wild-type HepG2 hepatocellular cancer cells in a time- and dose-dependent manner. Cetuximab treatment resulted in an increase of expression of the cyclin-dependent kinase inhibitors p21Waf1/CIP1 and p27Kip1 associated with a decrease in cyclin D1 expression. Additionally, we observed a moderate increase in apoptosis as demonstrated by caspase–3 activation. Combining cetuximab with an EGFR tyrosine kinase inhibitor (EGFR-TKI) resulted in synergistic antiproliferative effects. In contrast, p53 mutated Huh–7 hepatocellular cancer cells proved to be less sensitive towards cetuximab, but when combined with the EGFR-TKI a pronounced reduction of cell growth was observed.