Strategies for overcoming resistance to EGFR family tyrosine kinase inhibitors

The first-generation epidermal growth factor receptor tyrosine kinase inhibitors erlotinib and gefitinib have been incorporated into treatment paradigms for patients with advanced non-small cell lung cancer. These agents are particularly effective in a subset of patients whose tumors harbor activating epidermal growth factor receptor mutations. However, most patients do not respond to these tyrosine kinase inhibitors, and those who do will eventually acquire resistance that typically results from a secondary epidermal growth factor receptor mutation (e.g., T790M), mesenchymal–epithelial transition factor amplification, or activation of other signaling pathways. For patients whose tumors have wild-type epidermal growth factor receptor, there are several known mechanisms of initial resistance (e.g., Kirsten rat sarcoma viral oncogene homolog mutations) but these do not account for all cases, suggesting that unknown mechanisms also contribute. To potentially overcome the issue of resistance, next-generation tyrosine kinase inhibitors are being developed, which irreversibly block multiple epidermal growth factor receptor family members (e.g., afatinib [BIBW 2992] and PF-00299804) and/or vascular endothelial growth factor receptor pathways (e.g., BMS-690514 and XL647). In addition, drugs that block parallel signaling pathways or signaling molecules downstream of the epidermal growth factor receptor, such as the insulin-like growth factor-1 receptor and the mammalian target of rapamycin, are undergoing clinical evaluation. As drug resistance appears to be pleomorphic, combinations of drugs or drugs with multiple targets may be more effective in circumventing resistance.