EGFR Mutations and Tyrosine Kinase Inhibitors: Structural Insights and Therapeutic Advances

Abstract

Epidermal Growth Factor Receptor (EGFR) mutations are a major driver of nonsmall cell lung cancer (NSCLC), particularly among nonsmoking populations. Oncogenic mutations within the tyrosine kinase (TK) domain of EGFR play a critical role in activating downstream signaling pathways that promote tumor growth and survival. Targeting this domain has proven effective in developing therapeutic agents for NSCLC. However, treatment with these inhibitors often leads to acquired resistance due to secondary on-target mutations and activation of alternative pathways, making disease management increasingly challenging and necessitating continuous development of novel drugs and strategies. This review provides a comprehensive structural analysis of EGFR, highlighting key activating and resistance-associated mutations and their implications for drug resistance. It also examines mutation-driven resistance mechanisms and the current landscape of novel tyrosine kinase inhibitors (TKIs) in clinical development.