Mechanisms of resistance to EGFR tyrosine kinase inhibitors

Since the discovery that non-small cell lung cancer(NSCLC) is driven by epidermal growth factor receptor(EGFR) mutations, the EGFR tyrosine kinase inhibitors(EGFR-TKIs, e.g., ge fi tinib and elrotinib) have been effectively used for clinical treatment. However, patients eventually develop drug resistance. Resistance to EGFR-TKIs is inevitable due to various mechanisms, such as the secondary mutation(T790M), activation of alternative pathways(c-Met, HGF, AXL), aberrance of the downstream pathways(K-RAS mutations, loss of PTEN), impairment of the EGFR-TKIs-mediated apoptosis pathway(BCL2-like 11/BIM deletion polymorphism), histologic transformation, ATP binding cassette(ABC) transporter effusion, etc. Here we review and summarize the known resistant mechanisms to EGFR-TKIs and provide potential targets for development of new therapeutic strategies.