New strategies in overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer.

The management of non-small cell lung carcinoma (NSCLC) has been transformed by the observation that lung adenocarcinomas harboring mutations in epidermal growth factor receptor (EGFR) are uniquely sensitive to EGFR tyrosine kinase inhibitors (TKI). In these patients, acquired resistance to EGFR-TKI develops after a median of 10 to 14 months, at which time the current standard practice is to switch to conventional cytotoxic chemotherapy. Several possible mechanisms for acquired resistance have been identified, the most common being the development of an EGFR T790M gatekeeper mutation in more than 50% of cases. In this review, we discuss recent advances in the understanding of acquired TKI resistance in EGFR-mutant lung cancer and review therapeutic progress with second generation TKIs and combinations of targeted therapies. ©2011 AACR.