Rapidly Accelerated Fibrosarcoma kinases (RAF kinases) (RAF)

Rapidly Accelerated Fibrosarcoma (RAF) kinases, comprising A-RAF, B-RAF, and C-RAF, are essential serine/threonine kinases within the mitogen-activated protein kinase (MAPK) signaling cascade. These enzymes are typically activated by RAS GTPases and subsequently phosphorylate MEK, triggering a signaling relay that governs critical cellular processes such as growth, differentiation, and survival (UniProt P15056, P04049). In many cancers, RAF kinases are dysregulated through mutations or chromosomal rearrangements, such as the AGAP3::BRAF fusion, which involves the fusion of the AGAP3 N-terminus to the BRAF kinase domain starting at exon 9. This specific fusion results in the loss of the auto-inhibitory N-terminal domain, leading to constitutive, RAS-independent dimerization and activation of the kinase (PMID: 30333116). Pan-RAF inhibitors are designed to target multiple RAF isoforms and are particularly effective against these fusion-driven and dimer-dependent cancers. Unlike first-generation BRAF inhibitors, which can cause paradoxical pathway activation in cells with RAF fusions or RAS mutations, pan-RAF inhibitors (such as tovorafenib) effectively inhibit the dimeric forms of the enzyme (PMID: 32814731). These therapeutic agents are currently being utilized and investigated in various solid tumors, including low-grade gliomas and melanomas, where traditional monomer-selective inhibitors are less effective. The development of these inhibitors represents a significant advancement in precision oncology for patients harboring Class II BRAF alterations like AGAP3::BRAF.

Other names

RAF proto-oncogene serine/threonine-protein kinaseB-Raf proto-oncogeneC-Raf proto-oncogeneA-Raf proto-oncogeneAGAP3-BRAF fusionAGAP3::BRAFex9v-raf murine sarcoma viral oncogene homolog

Inhibition of the kinase activity of RAF isoforms (A-RAF, B-RAF, and C-RAF) to block the MAPK/ERK signaling pathway, specifically targeting both monomeric and dimeric forms of the kinases.