Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer

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Abstract
Epidermal growth factor receptor (EGFR)-mutant tumours define a unique subset of non-small-cell lung cancer (NSCLC). These tumours display sensitivity to small-molecule EGFR tyrosine kinase inhibitors (TKIs). Prospective clinical trials have now validated the correlation between EGFR mutation and TKI sensitivity. Multiple mechanisms of primary and secondary resistance of lung tumours to EGFR TKIs have been elucidated. Unfortunately, all patients eventually develop acquired resistance. Secondary mutations in EGFR and/or amplification of the gene encoding the MET receptor tyrosine kinase account for most cases of resistance. On the basis of promising preclinical data, many new rationally designed strategies are now being pursued in clinical trials to overcome acquired resistance. EGFR-mutant lung cancer can serve as a model for other cancers driven by oncogenic kinases.