Targeting BRAF in cancers - from molecular diagnostics to personalized therapy

Molecular profiling has become a cornerstone of cancer diagnosis and treatment, with BRAF alterations serving as significant markers across various tumor types. The gene encodes a serine/threonine kinase involved in the MAPK/ERK signaling pathway, which regulates cell proliferation and survival. Mutations in BRAF, notably the V600 codon substitutions, are among the most common genetic drivers in melanoma and other cancers, including thyroid, colorectal, and non-small cell lung cancer. BRAF mutations are categorized into three functional classes (class I-III), each with distinct activation mechanisms and therapeutic implications. Current targeted therapies - primarily BRAF and MEK inhibitors, including the first FDA-approved anti-BRAF tumor-agnostic therapy - are most effective in cancers harboring the class I V600E mutation. However, the emergence of resistance to BRAF inhibitors has driven the development of next-generation inhibitors and combination treatments. Furthermore, innovative immunotherapy-based treatments have demonstrated synergistic potential in specific BRAF-mutated malignancies. Accurate molecular diagnostics are crucial in cancer treatment; therefore, numerous molecular diagnostic methods are employed, including next-generation sequencing (NGS), quantitative PCR, droplet digital PCR, Sanger sequencing, and fluorescence in situ hybridization (FISH). NGS, particularly comprehensive genomic profiling, provides the broadest and most detailed genetic data, although simpler laboratory techniques remain popular due to their accessibility and straightforward protocols. Further research into resistance mechanisms and combination therapies, as well as the integration of circulating tumor DNA (ctDNA) in diagnostics, is needed to fully realize the potential of personalized treatment in BRAF-driven tumors.