Resistance mechanisms and overcoming strategies of the third-generation EGFR-TKI in non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) gene is the most common driver gene of non-small cell lung cancer. Tyrosine kinase inhibitors (TKIs) targeting EGFR mutations are the first-line treatment choice for patients with EGFR mutations. Although three generations of drugs have been widely used in clinical practice, unavoidable secondary resistance and primary resistance to some treatment-naive patients still pose great challenges to the long-term use of EGFR-TKIs. Resistance mechanism of the first- and second-generation EGFR-TKIs are well studied, including T790M mutation, MET amplification, ERBB2 amplification, IGF1R upregulation, AXL activation, etc. The third-generation TKIs can overcome the most common T790M mutation that the first two generations bring in, but with the increasingly widespread clinical use, their drug resistance problem is also attracting widespread attention, and the related mechanisms and overcoming strategies are still under study. Mechanisms can be divided into EGFRdependent and EGFR-independent ones, involving target-gene mutation, bypass signaling activation, phenotypic plasticity, epigenetic regulation, inhibitory immune microenvironment and so on. The fourth-generation TKIs, combination therapy and immunotherapy are all potential modalities after drug resistance. [ABSTRACT FROM AUTHOR]