EGFR Dysregulation in Cancer: From Molecular Mechanisms and Key Mutations to Evolving TKI Strategies and Resistance Mitigation

INTRODUCTION/OBJECTIVE: Regulation of cell growth, survival, and differentiation relies heavily on the epidermal growth factor receptor (EGFR). Dysregulations of EGFR signaling, whether due to overexpression or mutations, play a major role in the development of many cancers, particularly non-small cell lung cancer. In this review, we provide a comprehensive overview of EGFR biology, its signaling pathways, and strategies for therapeutic targeting. METHODS: This review combines the existing research on EGFR structure and its interactions with ligands, along with the signaling pathways that follow. It focuses on RAS/RAF/MEK/ERK and PI3K/AKT/mTOR axes, while considering JAK/STAT and PLCγ/PKC signaling. It alsofocuses on the triple mutant EGFR (L858R, T790M, and C797S) and discusses the therapeutic shift from first-generation reversible inhibitors to later generations of irreversible tyrosine kinase inhibitors. This review also examines a new wave of treatments. It explores fourth-generation TKIs and allosteric inhibitors alongside newer treatment strategies, such as PROTACs, combination immunotherapy, and precision medicine methods. RESULTS: For NSCLS patients with activating mutations, progress in EGFR-targeted treatments has transformed clinical outcomes. Due to the rise in resistance mechanisms, such as secondary mutations, the long-term effectiveness remains blocked. However, ongoing research on new treatment strategies reveals promising potential to overcome resistance and improve treatment effectiveness. DISCUSSION: Combining what we have learned about the EGFR at the molecular level with new therapeutic approaches highlights how valuable precision oncology has become in treating cancer. To improve treatment outcomes, we need to understand how pathways, mutations, and drug response interact with each other. CONCLUSION: In this review, we aim to outline current knowledge and future directions in EGFR-targeted therapy by providing insights into newer strategies and precision oncology.