Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors

The tyrosine kinase inhibitors(TKI) of the epidermal growth factor receptor(EGFR) are becoming the first line of therapy for advanced non-small cell lung cancer(NSCLC).Acquired mutations in EGFR account for one of the major mechanisms of resistance to the TKIs.Three generations of EGFRTKIs have been used in clinical applications.AZD9291(osimertinib;Tagrisso) is the first and only FDA approved third-generation EGFR TKI for T790M-positive advanced NSCLC patients.However,resistance to AZD9291 arises after 9-13 months of therapy.The mechanisms of resistance to third-generation inhibitors reported to date include the EGFR C797 S mutation,EGFR L718 Q mutation,and amplifications of HER-2,MET,or ERBB2.To overcome the acquired resistance to AZD9291,EAI045 was discovered and recently reported to be an allosteric EGFR inhibitor that overcomes T790M-and C797S-mediated resistance.This review summarizes recent investigations on the mechanisms of resistance to the EGFR TKIs,as well as the latest development of EAI045 as a fourth-generation EGFR inhibitor.