Rapidly accelerated fibrosarcoma (RAF) kinase family (RAF)

The Rapidly Accelerated Fibrosarcoma (RAF) family consists of three serine/threonine-protein kinases—ARAF, BRAF, and CRAF (RAF-1)—that serve as critical nodes in the mitogen-activated protein kinase (MAPK) signaling pathway (UniProt, 2024). These kinases are recruited to the plasma membrane by activated RAS, where they dimerize and phosphorylate MEK1/2, ultimately leading to the activation of ERK1/2 and the regulation of gene expression for cell growth, differentiation, and survival (Davies et al., 2002). BRAF is the most frequently mutated member in human oncology, with the V600E mutation occurring in approximately 50% of melanomas and varying percentages of colorectal, thyroid, and lung cancers (National Cancer Institute, 2023). This mutation results in constitutive, RAS-independent kinase activity that drives malignant transformation. Therapeutic intervention primarily utilizes small-molecule inhibitors like vemurafenib, dabrafenib, and encorafenib, which target the active conformation of the mutant kinase (Subbiah et al., 2020). A notable challenge in RAF-targeted therapy is the "paradoxical activation" of the MAPK pathway in BRAF wild-type cells, which can lead to secondary malignancies such as cutaneous squamous cell carcinoma (StatPearls, 2023). To mitigate this and overcome acquired resistance, BRAF inhibitors are commonly combined with MEK inhibitors in clinical practice (PubMed, 2021).

Other names

B-Raf proto-oncogenev-Raf murine sarcoma viral oncogene homolog BRAF1ARAFC-RafProto-oncogene c-RAFBRAF1RAFB1

ATP-competitive inhibition of the RAF kinase domain, preventing the phosphorylation of downstream MEK proteins in the MAPK signaling pathway.