Rapidly Accelerated Fibrosarcoma (RAF) family dimer (RAF dimer)

The Rapidly Accelerated Fibrosarcoma (RAF) family dimer, consisting of homo- and heterodimers of ARAF, BRAF, and CRAF, is a critical mediator in the RAS-RAF-MEK-ERK signaling pathway (Source: UniProt). Dimerization is a mandatory step for the activation of RAF kinases, typically triggered by the binding of active RAS-GTP at the plasma membrane (Source: Nature Reviews Molecular Cell Biology, 2019). This molecular event facilitates the transphosphorylation and activation of downstream MEK proteins, which in turn activate ERK to regulate gene expression and cellular growth. In oncogenic states, such as those driven by RAS mutations or BRAF fusions, constitutive dimerization leads to persistent MAPK pathway signaling, promoting tumor growth and survival (Source: PubMed PMID: 22237106). A significant challenge with first-generation RAF inhibitors (e.g., vemurafenib) is their tendency to induce "paradoxical activation" by promoting the formation of CRAF-containing dimers in RAS-mutant cells, which can lead to secondary skin cancers (Source: NEJM, 2012). Consequently, next-generation "dimer-breaking" or pan-RAF inhibitors are being developed to target these dimeric forms more effectively across various oncogenic contexts, including RAS-mutant and BRAF-mutant cancers (Source: Journal of Clinical Oncology, 2021).

Other names

RAF kinase dimerBRAF-CRAF heterodimerBRAF-BRAF homodimerCRAF-CRAF homodimerARAF-BRAF heterodimerRAF homo- and heterodimer

Inhibition of the kinase activity of RAF homo- and heterodimers, or prevention of the dimerization process itself, to block downstream MEK/ERK signaling (Source: Nature Reviews Drug Discovery, 2020).