The evolving horizon: acquired resistance to third-generation EGFR-TKIs and emerging next-generation EGFR inhibitors

Abstract The discovery that mutations in the EGFR gene are detected in up to 50% of lung adenocarcinoma patients, along with the development of highly efficacious EGFR tyrosine kinase inhibitors (TKIs), has revolutionized the treatment of this frequently occurring lung malignancy. Indeed, the clinical success of these TKIs constitutes a critical milestone in targeted cancer therapy. Three generations of EGFR TKIs are currently approved for the treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC). The first-generation TKIs include Erlotinib, Gefitinib, Lapatinib and Icotinib; the second-generation ErbB family blockers include Afatinib, Neratinib and Dacomitinib; whereas Osimertinib approved by the FDA on 2015, is a third-generation TKI targeting EGFR harboring specific mutations. Compared to the first- and second-generation TKIs, third-generation EGFR inhibitors display a significant advantage in terms of patient survival. For example, the median overall survival in NSCLC patients receiving Osimertinib reached 38.6 months. Unfortunately, however, like other targeted therapies, new EGFR mutations, as well as additional drug resistance mechanisms emerge rapidly after treatment, posing formidable obstacles towards cancer therapeutics aimed at surmounting this chemoresistance. In the current review, we summarized the molecular mechanisms underlying resistance to third-generation EGFR inhibitors and the ongoing efforts to address and overcome this chemoresistance. We also discuss the current status of fourth-generation EGFR inhibitors, which are of great value in overcoming resistance to EGFR inhibitors which appear to have greater therapeutic benefits in the clinics.