Targeting of the EGFR As a Modulator of Cancer Chemotherapy

Abstract

The epidermal growth factor (EGF) receptor (EGFR) is a tyrosine kinase receptor of the ErbB family that is abnormally activated in many epithelial tumors. In human tumors, receptor overexpression correlates with a more aggressive clinical course. These observations suggest that the EGFR is a promising target for cancer therapy, and monoclonal antibodies directed at the ligand-binding extracellular domain and low molecular weight (MW) inhibitors of the receptor’s tyrosine kinase inhibitors (TKI) are currently in advanced stages of clinical development. These agents prevent ligand-induced receptor activation and downstream signaling, which results in cell-cycle arrest, promotion of apoptosis, and inhibition of angiogenesis. In preclinical models, these agents markedly enhance the antitumor effects of chemotherapy and radiation therapy. In patients, anti-EGFR agents can be given safely at doses that fully inhibit receptor signaling, and single-agent activity has been observed against a variety of tumor types, including colon carcinoma, non-small-cell lung cancer (NSCLC), head and neck cancer, ovarian carcinoma, and renal-cell carcinoma. However, their antitumor activity is significant but modest, and to improve their efficacy, ongoing research efforts are being directed at the selection of patients with EGFR-dependent tumors, identification of the differences among the various classes of agents, and new clinical development strategies. One such strategy, derived from the preclinical models, is to combine these agents with chemotherapy. Clinical trials of anti-EGFR agents in combination with chemotherapy have been conducted or are underway in a variety of tumor types and in different clinical settings. In NSCLC, a series of well-supported multinational phase III clinical trials have shown that the combined therapy with chemotherapy and anti-EGFR TKI is not superior to chemotherapy alone. On the other hand, in advanced colorectal cancer, the combined treatment with anti-EGFR monoclonal antibodies and conventional chemotherapy was found to be statistically superior in terms of disease-free survival when compared with chemotherapy alone. In addition, in smaller trials, the addition of anti-EGFR monoclonal antibodies to chemotherapy does result in a higher antitumor response rate than with chemotherapy alone. Taken together, anti-EGFR agents are active antitumor agents, and the optimal way to combine these agents with conventional chemotherapy is still to determined and likely to be agent and tumor-type dependent. Intensive clinical research on how best to integrate these agents into treatment is warranted.KeywordsEpidermal Growth Factor ReceptorClin OncolTyrosine Kinase InhibitorMutant Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor ExpressionThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.