Resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

Treatment with epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs) prolongs the overall survival of patients with EGFR-mutated advanced non-small-cell lung cancer(NSCLC). EGFR-TKIs including first-generation(e.g., gefitinib and erlotinib), second-generation(e.g., afatinib and dacomitinib) and third-generation(e.g., osimertinib) drugs are effective for the treatment of EGFR-mutated NSCLC. However, almost all patients exhibit drug failure related to resistance including primary and acquired resistance. Several mechanisms involved in primary and acquired resistance to EGFR-TKIs have been reported recently. Primary resistance to EGFR-TKIs involves point mutations in exon 18, deletions or insertions in exon 19, insertions, duplications and point mutations in exon 20 and a point mutation in exon 21 of the EGFR gene. Acquired resistance to EGFR-TKIs can be characterized into two groups: resistance to first-and second-generation EGFR-TKIs, and resistance to third-generation EGFR-TKIs. The third-generation EGFR-TKI resistance group presents a complex model including EGFR C797 S mutations, erb-b2 receptor tyrosine kinase 2 gene(ERBB2) amplification, BRAF V600 E mutations, ROS1 fusion, and MNNG HOS transforming gene(c-Met) amplification. Personalized diagnosis and monitoring as well as the development of next generation drugs are desperately needed for better survival outcomes in EGFR mutant NSCLC patients. In this article, we review these mechanisms and discuss the latest therapeutic strategies to overcome resistance to EGFR-TKIs.