RAF kinase family (ARAF, BRAF, and CRAF) (RAF)

The RAF kinase family, which includes the isoforms A-RAF, B-RAF, and C-RAF (also known as RAF1), consists of serine/threonine-specific protein kinases that serve as essential mediators in the Ras-Raf-MEK-ERK (MAPK) signaling cascade [1, 6, 9]. This pathway is fundamental to cellular communication, translating extracellular signals from growth factors and hormones into nuclear responses that govern cell proliferation, differentiation, and survival [1, 2, 4]. Under normal physiological conditions, RAF kinases are activated through recruitment to the plasma membrane by GTP-bound Ras, followed by complex dimerization and phosphorylation events [6, 17]. However, oncogenic mutations—most frequently the BRAF V600E substitution—lead to constitutive, Ras-independent kinase activity that drives uncontrolled tumor growth in various cancers, including melanoma, colorectal, and non-small cell lung cancer [3, 5, 13, 15]. Pharmacological targeting of RAF kinases has evolved from first-generation inhibitors that selectively target mutant BRAF monomers to next-generation pan-RAF inhibitors designed to block both mutant and wild-type RAF dimers [8, 12, 14, 16]. While selective BRAF inhibitors have revolutionized the treatment of V600-mutant melanoma, they can cause paradoxical activation of the MAPK pathway in cells with wild-type RAF and upstream Ras mutations, potentially leading to secondary cutaneous malignancies [8, 17, 18]. Pan-RAF inhibitors aim to circumvent this issue and address resistance mechanisms by providing broader coverage across the RAF family [8, 9, 16]. Clinical management of patients receiving these therapies requires careful monitoring for side effects such as pyrexia, rash, and photosensitivity, as well as the use of molecular biomarkers like BRAF mutation status to guide treatment selection [5, 7, 10, 18].

Other names

B-RafC-RafA-RafRAF1BRAF1NS7v-Raf murine sarcoma viral oncogene homolog

RAF inhibitors bind to the ATP-binding pocket of the kinase domain, inhibiting the enzymatic activity of RAF isoforms (A-RAF, B-RAF, and C-RAF) [17]. This blockade prevents the phosphorylation of downstream MEK and ERK proteins, effectively shutting down the MAPK/ERK signaling cascade [1, 6]. Type I inhibitors (e.g., vemurafenib) are selective for the active conformation of mutant BRAF monomers, whereas Type II and pan-RAF inhibitors (e.g., tovorafenib, belvarafenib) target both mutant and wild-type RAF in their dimeric forms, which helps to avoid the paradoxical activation of the pathway in cells with wild-type RAF and upstream RAS mutations [8, 16, 17].