Opportunities and challenges in the development of evolving EGFR inhibitors to overcome EGFR TKIs resistance.

Abnormal EGFR signaling is considered the cause of the occurrence and development of EGFR-addicted NSCLC. EGFR tyrosine kinase inhibitors (TKIs) have dramatically revolutionized the treatment landscape of NSCLC patients over the past two decades. Most patients with EGFR-activating mutations (such as deletions in exon 19 and the L858R substitution mutation) initially respond to the first-generation of EGFR TKIs, but acquired resistance will inevitably emerge during clinical treatment, most frequently owing to the secondary T790M mutation within the ATP binding site of the receptor. As second-generation TKIs have demonstrated limited clinical efficacy against EGFR T790M-mediated resistance, third-generation TKIs with improved selectivity have spurred intensive research efforts. However, tertiary EGFR C797S mutation-mediated resistance to third-generation of EGFR TKIs remains an unmet clinical need. Moreover, EGFR exon 20 insertion (exon20ins) mutations are insensitive to prior EGFR-TKIs and are associated with poor prognosis; consequently, novel inhibitors targeting these mutations are gaining traction. Moreover, tumor heterogeneity and complexity contribute to EGFR TKIs resistance through mechanisms such as bypass pathway activation, histological transformation, and emerging metabolic reprogramming. Therefore, the development of novel EGFR TKIs and the identification of potential combination therapies to overcome EGFR TKIs resistance have attracted significant attention. Here, we review the historical progress in the development of EGFR TKIs and "on-target"-mediated and EGFR-independent resistance mechanisms, aiming to summarize the current status of and provide future directions for EGFR TKI research.