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 BRAF^V600E, 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.