Precision Oncology in Non-Small Cell Lung Cancer: Integrating Molecular Diagnostics, Targeted Therapies, and Resistance Mechanisms

Abstract

Background: Precision oncology has significantly transformed the management of non-small cell lung cancer (NSCLC) through the integration of molecular diagnostics, targeted therapies, and biomarker-driven treatment selection. Advances in next-generation sequencing (NGS) and liquid biopsy have improved the identification of actionable molecular alterations and enabled dynamic monitoring of tumor evolution. Objective: To provide a structured narrative review of current evidence regarding actionable molecular biomarkers, diagnostic methodologies, targeted therapies, and future directions in NSCLC precision oncology, with a specific focus on conceptualizing acquired resistance mechanisms. Methods: A structured narrative literature review was conducted by searching PubMed and Google Scholar for English-language studies published between 2015 and 2026. Eligible publications included clinical trials, cohort studies, translational research, reviews, and clinical guidelines addressing molecular profiling, targeted treatments, diagnostic approaches, and resistance mechanisms in NSCLC. Results: A total of 99 foundational studies and clinical documents were analyzed. Key actionable biomarkers included EGFR (Epidermal Growth Factor Receptor), ALK (Anaplastic Lymphoma Kinase), ROS1 (ROS Proto-Oncogene 1, Receptor Tyrosine Kinase), KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog), RET (Rearranged during Transfection), MET (Mesenchymal–Epithelial Transition Factor), HER2 (Human Epidermal Growth Factor Receptor 2) and NTRK (Neurotrophic Tyrosine Receptor Kinase) alterations, along with emerging targets such as NRG1 (Neuregulin 1) fusions. NGS emerged as the cornerstone of comprehensive molecular profiling, while liquid biopsy enabled longitudinal monitoring of tumor dynamics and resistance development. To organize the biological complexity of treatment failure, acquired resistance mechanisms were categorized into a three-tiered conceptual framework: target-centric genetic evolution (Tier 1), cellular plasticity and intratumoral heterogeneity (Tier 2), and non-genetic/microenvironmental adaptation (Tier 3). Targeted therapies significantly improved clinical outcomes compared with conventional chemotherapy; however, acquired resistance remained a major challenge across all tiers. Conclusions: Precision oncology in NSCLC is evolving from a biomarker-focused approach toward a dynamic framework integrating molecular diagnostics, targeted therapies, and continuous resistance monitoring. The proposed three-tiered resistance framework provides a structured basis for understanding treatment failure, guiding molecular reassessment at progression, and informing future adaptive therapeutic strategies to improve long-term patient outcomes.