Targeting BRAF dimerization in cancer: structural insights and therapeutic strategies beyond monomer inhibition.

The mitogen-activated protein kinase (MAPK) signaling pathway is a central oncogenic signaling axis, with BRAF functioning as a critical regulatory node. The discovery of oncogenic BRAF mutations, most notably BRAFV600E, enabled the development of targeted therapies that significantly improved clinical outcomes in several cancers. However, extensive preclinical and clinical investigations have revealed fundamental limitations of interpreting RAF signaling from a monomer-centric perspective. Rather than acting solely as an isolated kinase, BRAF exists in a dynamic equilibrium between inactive monomers and active dimers, with dimerization emerging as a major determinant of MAPK pathway output, therapeutic response, and resistance. In this review, we integrate structural, mechanistic, and translational evidence to establish BRAF dimerization as a central organizing principle of RAF signaling. These structural insights are placed in a disease context by examining how distinct classes of BRAF mutations constitutively active, dimer-dependent, or kinase-impaired converge on dimer-mediated MAPK activation. We further discuss molecular mechanisms that promote dimerization-driven therapeutic resistance, including alternative BRAF splicing, gene amplification, receptor tyrosine kinase RAS feedback activation, and scaffold-mediated stabilization of RAF dimers. Finally, we evaluate emerging therapeutic strategies targeting dimeric RAF complexes, including pan-RAF and dimer-compatible inhibitors, allosteric modulators, interface disruptors, and targeted protein degradation approaches, alongside mutation-class informed clinical trial designs and biomarker-adaptive strategies. Collectively, this review positions BRAF dimerization as a fundamental and therapeutically actionable feature of MAPK signaling, providing a structural and clinical framework for the development of durable RAF-targeted therapies beyond monomer inhibition.