The field of non-small cell lung cancer (NSCLC) therapy has been drastically altered by the introduction of epidermal growth factor receptor (EGFR)-targeted therapies. The discovery of activating EGFR mutations revolutionized patient management, leading to the development of highly effective tyrosine kinase inhibitors (TKIs) that have significantly improved progression-free survival and quality of life for many patients. Progressing from first to third-generation TKIs like osimertinib, the evolution of these therapies has not only informed our theoretical understanding of EGFR signaling pathways but has also set new standards in personalized patient care.

Despite these advancements, a major barrier remains in the form of acquired resistance to EGFR-TKIs. This resistance emerges through complex biological mechanisms, including secondary mutations within EGFR itself and alternative signaling pathways independent of EGFR. As a result, the focus is shifting towards innovative therapeutic strategies that combine mono-therapy approaches with next-generation treatments, addressing resistance by targeting both EGFR-dependent and independent pathways.

This Research Topic aims at providing an interdisciplinary platform where the convergence of molecular regulation studies and clinical practice advancements are explored to enhance precision lung cancer treatments. We strive to compile breakthrough discoveries that address resistance challenges, optimize treatment efficacy, and refine methodologies for personalized therapy.

To gather further insights in EGFR-targeted therapy's multifaceted aspects, we welcome articles addressing, but not limited to, the following themes:

• Molecular Mechanisms of EGFR Signaling and Oncogenesis: Detailed studies on EGFR activating mutations (common, uncommon, and complex variants) and their impact on downstream signaling pathways (e.g., RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, JAK/STAT).
• Mechanisms of Acquired and Intrinsic EGFR-TKI Resistance: Elucidation of novel EGFR-dependent (e.g., C797S and other tertiary mutations) and EGFR-independent resistance mechanisms (e.g., alternative pathway activation, histological transformation to SCLC/LCNEC).
• Advancing Clinical Practice and Therapeutic Strategies: Evaluation of current and emerging first-line and subsequent-line treatment strategies, including the latest clinical trial data for combination therapies (e.g., TKI + chemotherapy, TKI + other targeted agents, TKI + immunotherapy) .
• Biomarkers and Personalized Medicine: The utility of comprehensive molecular profiling (e.g., Next-Generation Sequencing) and liquid biopsy (cfDNA) for dynamic monitoring of disease progression, resistance, and guiding treatment decisions.
• Translational Research and Future Directions: Bridging preclinical discoveries with clinical translation, including the development of novel drug delivery systems and therapeutic targets.

This Research Topic will consider original research, reviews, systematic reviews, methods, perspectives, opinions, and case reports.

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EGFR-Targeted Therapy in Lung Cancer: Unraveling Molecular Regulation, Overcoming Resistance, and Advancing Precision Clinical Practice