Unveiling BRAF mutations in non-small cell lung cancer: state of the art and future perspectives

Lung cancer is the most frequently diagnosed malignancy worldwide in recent decades, accounting for approximately 12.4% of all cancers and representing the leading cause of cancer-related mortality globally. Lung cancer is mainly divided into two types, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), with NSCLC being the most common, representing about 85% of cases. NSCLC is increasingly recognized to harbor various druggable genetic alterations, including mutations or fusions in genes such as EGFR, BRAF, KRAS, ALK, ROS1, MET, RET, HER2, NRG1, and NTRK, each driving specific cancer-promoting pathways. Activating BRAF mutations are found in approximately 3-4% of NSCLC patients, the majority being the V600E variant, which permits treatment with approved BRAF inhibitors, either as monotherapy or in combination with MEK inhibitors. The objective of this review is to provide a comprehensive overview of the key biological and pathophysiological characteristics of BRAF molecular alterations, their impact on contemporary clinical practice, and emerging insights from translational research. Despite notable advances in targeted therapies and immunotherapy for BRAF‑mutant NSCLC, treatment resistance and limited clinical data, particularly in first line and neoadjuvant settings, remain major challenges. Several ongoing studies are currently evaluating novel agents with broader biological activity and various drug combinations. Emerging strategies, including next-generation MAPK inhibitors, ADCs, and engineered cellular therapies such as CAR‑T, CAR‑NK, and CAR‑M, offer promising avenues to enhance efficacy, overcome resistance, and expand therapeutic options for these patients.