The family of RAF kinases (ARAF, BRAF and CRAF (also known as RAF1)) constitute core components of the RAS–RAF–MEK–ERK signalling cascade (ERK signalling), a pathway that mediates signals from cell surface receptors to the nucleus to regulate cell growth, differentiation and survival. Upon activation, RAF kinases phosphorylate and activate the kinases MEK1 and MEK2, which in turn phosphorylate and activate ERK1 and ERK2. Activated ERK promotes cell proliferation and survival by phosphorylating multiple substrates both in the cytosol and in the nucleus. RAS protein has been extremely difficult to target, and thus the downstream kinases RAF, MEK and ERK remain attractive therapeutic targets in such tumours, although current inhibitors of these kinases have only showed limited efficacy in RAS-mutant cancers.
 Canonical RAF activation is regulated by members of the RAS family of small GTPases (KRAS, NRAS and HRAS), which, upon growth factor stimulation of upstream receptors, are converted from the inactive (RAS-GDP) to the active (RAS-GTP) form in the plasma membrane. BRAF mutations are present in approximately 8% of human tumours, which is commonly mutated in melanomas (50%), papillary thyroid cancers (45%), colon cancers (10%), non-small-cell lung cancers (NSCLCs) (10%), in virtually 100% of hairy cell leukemias and in 50–60% of patients with the idiopathic disorder Langerhans cell histiocytosis (LCH). Dependence of BRAF-V600E tumours on BRAF and ERK signalling activity supported the therapeutic benefit of targeting ERK signalling in cancer and intensified efforts for the development of selective ATP-competitive inhibitors of mutant BRAF kinase.


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