%0 Journal Article
%T The resistance landscape of EGFR tyrosine kinase inhibitors in advanced non-small cell lung cancer: molecular mechanisms and novel therapeutic strategies
%A Liu, Shuotong
%A Zhou, Linsen
%A He, Yongze
%A Liu, Qianyi
%A Tang, Ying
%A Liu, Zhen
%A Zeng, Xianhu
%A Li, Jiangping
%J Translational Lung Cancer Research
%D 2026
%B 2026
%9 
%! The resistance landscape of EGFR tyrosine kinase inhibitors in advanced non-small cell lung cancer: molecular mechanisms and novel therapeutic strategies
%K 
%X Lung cancer remains the leading cause of global cancer-related mortality, with non-small cell lung cancer (NSCLC) constituting the predominant histological subtype. The discovery of epidermal growth factor receptor (EGFR) as a driver oncogene and elucidation of its mechanism of action through three canonical signaling pathways have driven the evolution of tyrosine kinase inhibitors (TKIs) from first to third generation. Following this breakthrough, EGFR-TKIs have revolutionized the treatment landscape for advanced EGFR-mutant NSCLC, significantly improving patient outcomes compared to conventional chemotherapy. However, the development of acquired resistance to EGFR-TKIs presents a major clinical challenge, ultimately limiting their long-term efficacy. Understanding this evolutionary trajectory and the architectural logic of the underlying signaling network lays the foundation for deciphering resistance mechanisms and designing next-generation therapeutic strategies. This comprehensive review systematically examines the molecular mechanisms underlying both intrinsic and acquired resistance to EGFR-TKIs, with a particular focus on third-generation agents like osimertinib. Key resistance mechanisms encompass on-target EGFR modifications (including tertiary C797S mutations and T790M loss), activation of bypass signaling pathways (such as MET, HER2, and AXL amplification), downstream pathway alterations (involving KRAS/BRAF and PI3K/AKT/mTOR cascades), and histologic transformations [including small cell lung cancer (SCLC) transformation and epithelial-mesenchymal transition (EMT)]. The review further explores current and emerging strategies to overcome these resistance mechanisms, including the development of fourth-generation TKIs, rational combination therapies targeting parallel pathways, and biomarker-guided treatment approaches. Understanding the complex landscape of EGFR-TKI resistance is paramount for developing novel therapeutic strategies and optimizing clinical outcomes for patients with advanced EGFR-mutant NSCLC.
%U https://tlcr.amegroups.org/article/view/116524
%V 15
%N 4
%P 101
%@ 2226-4477