Oncogenic drivers in nonsmall cell lung cancer and resistance to epidermal growth factor receptor tyrosine kinase inhibitors

Nonsmall cell lung cancer (NSCLC) is increasingly being treated with targeted therapies. Epidermal growth factor receptor (EGFR) has been extensively studied in NSCLC as an oncogenic driver. However, the efficacy of the EGFR tyrosine kinase inhibitors (TKIs) is adversely impacted by the development of resistance. The occurrence of de novo resistance to EGFR TKIs is attributed to multiple mechanisms such as point mutations of oncogenes and chromosomal rearrangements. The development of acquired resistance to EGFR TKIs is facilitated by secondary mutations, phenotypical transformation, aberrance of downstream pathways, and activation of alternate signaling pathways. The T790M mutation is the most common mutation that accounts for about half of the acquired resistance to EGFR TKIs. This review article provides an overview of the common oncogenic drivers, targeted therapies for NSCLC, and the established mechanisms implicated in the development of resistance to the EGFR TKIs.