Mechanisms and management of 3rd-generation EGFR-TKI resistance in advanced non-small cell lung cancer (Review)

Targeted therapy with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is a standard modality of the 1st-line treatments for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC), and substantially improves their prognosis. However, EGFR T790M mutation is the primary mechanism of 1st- and 2nd-generation EGFR-TKI resistance. Osimertinib is a representative of the 3rd-generation EGFR-TKIs that target T790M mutation, and has satisfactory efficacy in the treatment of T790M-positive NSCLC with disease progression following use of 1st- or 2nd-generation EGFR-TKIs. Other 3rd-generation EGFR-TKIs, such as abivertinib, rociletinib, nazartinib, olmutinib and alflutinib, are also at various stages of development. However, the occurrence of acquired resistance is inevitable, and the mechanisms of 3rd-generation EGFR-TKI resistance are complex and incompletely understood. Genomic studies in tissue and liquid biopsies of resistant patients reveal multiple candidate pathways. The present review summarizes the recent findings in mechanisms of resistance to 3rd-generation EGFR-TKIs in advanced NSCLC, and provides possible strategies to overcome this resistance. The mechanisms of acquired resistance mainly include an altered EGFR signaling pathway (EGFR tertiary mutations and amplification), activation of aberrant bypassing pathways (hepatocyte growth factor receptor amplification, human epidermal growth factor receptor 2 amplification and aberrant insulin-like growth factor 1 receptor activation), downstream pathway activation (RAS/RAF/MEK/ERK and PI3K/AKT/mTOR) and histological/phenotypic transformations (SCLC transformation and epithelial-mesenchymal transition). The combination of targeted therapies is a promising strategy to treat osimertinib-resistant patients, and multiple clinical studies on novel combined therapies are ongoing.

Automated summary

Targeted therapy with EGFR-TKIs is standard for advanced EGFR-mutated NSCLC, with osimertinib being a representative 3rd-generation TKI for T790M-positive patients. However, complex resistance mechanisms including altered signaling pathways and cellular transformations challenge treatment efficacy, highlighting the need for novel combination therapies in addressing acquired resistance.