The EGF receptor (EGFR) is involved in the pathogenesis of human carcinoma. Two classes of EGFR antagonists are currently in clinical use, anti-EGFR monoclonal antibodies (mAbs) and small-molecule EGFR tyrosine kinase inhibitors (TKIs). Anti-EGFR mAbs prevent ligand binding; inhibit receptor activation; induce dimerization, internalization and downregulation of the EGFR; and activate a host immune response. EGFR TKIs directly inhibit tyrosine kinase phosphorylation by physical interaction with either the ATP and/or the enzyme substrate binding sites. Anti-EGFR drugs are extremely active in subgroups of patients whose tumors depend on EGFR for growth and survival. Non-small-cell lung cancer sensitive to EGFR TKIs carry activating mutations of the EGFR. Patients that initially respond to anti-EGFR agents usually become resistant to these drugs. Several different mechanism have been shown to produce acquired resistance to anti-EGFR drugs. Preliminary results suggest that genetic mechanisms of resistance might be lost in the absence of the continued selective pressure of EGFR inhibitor treatment.
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