Junhui Wang, Jian Wang, Jianxin Chen
Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) have revolutionized the treatment landscape for Non-Small Cell Lung Cancer (NSCLC). However, resistance invariably curtails their long-term efficacy. This comprehensive review delineates the intricate mechanisms underpinning EGFR TKI resistance and the evolving therapeutic counterstrategies. We present a panoramic atlas of resistance mechanisms, encompassing on-target resistance, bypass pathway activation, histologic transformation, and metabolic reprogramming, alongside their clinical classification. The discussion extends to the integrated diagnostic technologies facilitating resistance detection, including multi-dimensional biopsy approaches and multi-omics fusion analysis. We critically evaluate precision therapeutic approaches tailored to specific resistance alterations, such as C797S mutations and mesenchymal-epithelial transition amplification, and explore the burgeoning field of novel agents like fourth-generation TKIs and antibody-drug conjugates (ADCs). Furthermore, innovative combination strategies and the challenges within resistance management systems, including toxicity profiles and unresolved scientific questions, are examined. A profound understanding of EGFR resistance mechanisms and the continuous refinement of therapeutic paradigms are paramount for improving the prognosis of NSCLC patients.