Overcoming resistance to third-generation epidermal growth factor receptor tyrosine kinase inhibitor in non-small cell lung cancer

In the treatment of non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations, EGFR-tyrosine kinase inhibitor (EGFR-TKI) is a key drug that can prolong the survival of patients. However, resistance to EGFR-TKIs has become a new problem that must be solved. All patients with NSCLCs with an EGFR mutation who have been treated with first- and second-generation EGFR-TKIs eventually exhibit disease progression, even if they have had a long period of response to the EGFR-TKI treatment. To overcome this resistance, various mechanisms for the acquisition of the resistance to first- and second-generation EGFR-TKIs have been identified, including second site mutation in EGFR, bypass mechanism of other pathways (such as MET amplification, PIK3CA mutation, and BRAF mutation), and transformation to small cell lung cancer. T790M second site mutation is the most frequently detected mechanism in recurrent EGFR mutant NSCLCs after first-line EGFR-TKI treatment. This second site mutation is substitution of threonine to methionine at the 790 site of exon 20, leading structural change in the ATP binding site of EGFR. T790M is called a “gate-keeper mutation” and is responsible for approximately 60% of acquired resistance to first- and second-generation EGFR-TKIs