Molecular Targeted Therapy of Lung Cancer: EGFR Mutations and Response to EGFR Inhibitors

Abstract

Somatic mutations within the kinase domain of the epidermal growth factor receptor (EGFR) are present in approximately10% of non-small-cell lung cancer (NSCLC), with an increased frequency in adenocarcinomas arising in nonsmokers, women,and individuals of Asian ethnicity. These mutations lead to altered downstream signaling by the receptor and appear to definea subset of NSCLC characterized by "oncogene addiction" to the EGFR pathway, which displays dramatic responses to thereversible tyrosine kinase inhibitors gefitinib and erlotinib. The rapid acquisition of drug resistance in most cases, eitherthrough mutation of the "gateway" residue in the EGFR kinase domain or by alternative mechanisms, appears to limit the impacton patient survival. Irreversible inhibitors of EGFR display continued effectiveness in vitro against cells with acquiredresistance and are now undergoing genotype-directed clinical trials. The molecular and clinical insights derived from targetingEGFR in NSCLC offer important lessons for the broader application of targeted therapeutic agents in solid tumors.