Precision treatment after resistance to first-generation EGFR-TKI in patients with non-small cell lung cancer

Abstract

Recently, with the research progress in molecular classification, the treatment of advanced non-small cell lung cancer (NSCLC) has been established as a model of anti-tumor treatment of precision medicine. The discovery of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) has transformed the treatment of NSCLC from platinum based doublet chemotherapy into era of target therapy. EGFR-TKI, such as erlotinib and gefitinib, have been recommended as standard first-line treatment of patients with EGFR mutation. However, acquired resistance, defined as tumor progression after initial response, seems to be an inevitable consequence of this treatment approach. Clinical modes of EGFR-TKI failure are classified into three types: dramatic progression, gradual progression and local progression. A threonine-to-methionine substitution (T790M) in exon 20 of the EGFR gene is the most common mechanism of resistance. Other mechanisms of resistance include MET amplification, epithelial to mesenchymal transition, small cell transformation, and PIK3CA mutation. This brief comment will provide an overview of the complex and heterogeneous problem of acquired resistance to EGFR-TKI therapy in NSCLC, and the clinical treatment options and new targeted drugs overcoming EGFR-TKI acquired resistance.