Natural Products for Overcoming EGFR-TKI Resistance in NSCLC: A Narrative Review

Introduction: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has transformed the treatment of non-small cell lung cancer (NSCLC), yet acquired resistance remains a major challenge to its clinical efficacy. This review summarizes current advances in overcoming EGFR-TKI resistance with natural products and further discusses the emerging role of targeted protein degradation (TPD) as a complementary strategy to enhance the selective and irreversible clearance of resistant proteins. Methods: We conducted a comprehensive literature review using the PubMed database with the keywords "natural products", "drug resistance", "EGFR-TKI", "targeted protein degradation", and "non-small cell lung cancer". Results: Cumulative evidence indicates that a variety of natural products can reverse or mitigate EGFR-TKI resistance in NSCLC via multitarget modulation. These compounds have been shown to influence EGFR mutations, inhibit aberrant signaling pathways such as Phosphatidylinositol 3-Kinase (PI3K)/ Protein kinase B (PI3K/AKT), block histologic and phenotypic transformation, and reduce drug efflux. Moreover, natural product- based TPD approaches have shown initial promise in their potential to degrade resistance-associated targets and may enhance TKI sensitivity, hinting at possible therapeutic advantages. Discussion: The reviewed evidence collectively supports the versatility of natural products in counteracting EGFR-TKI resistance. Integration with TPD strategies appears synergistic and may help address the limitations of single-agent therapy. Conclusion: Natural products, particularly when combined with TPD approaches, represent a promising strategy for overcoming EGFR-TKI resistance in NSCLC and may contribute to the development of more effective targeted therapies.