UCSF

Key PointsMutationally activated BRAF is expressed in melanoma, glioblastoma, thyroid, lung and colon cancers and in a subset of haematological malignancies.The most common BRAF mutation leads to the substitution of a glutamic acid for valine at amino acid 600 (V600E) in the kinase domain of the protein. This substitution mimics phosphorylation of the activation loop, thereby inducing constitutive BRAF protein kinase activity.Point mutations in the related ARAF and CRAF protein kinases, although very rare, have been reported as oncogenic drivers in some human cancers. In addition to point mutation, gene fusion events are reported to activate BRAF and CRAF.Numerous non-V600E alterations in BRAF have been reported in cancer and in a rare developmental disorder. Many of these promote kinase activity by relieving autoinhibitory mechanisms or promote activation of other RAF isoforms in a RAS-dependent manner.ATP-competitive BRAF kinase inhibitors are currently under investigation for the treatment of BRAF-mutated cancers. However, to date, efficacy is limited to a subset of melanomas owing to primary or adaptive resistance mechanisms in colorectal and thyroid cancers that reactivate signalling downstream of receptor tyrosine kinases.In clinical trials of BRAF-mutated melanoma, BRAF inhibitors tend to induce high rates of response that show transient durability due to the onset of drug-resistant disease.Acquired resistance to BRAF-V600E inhibitors is strikingly complex but frequently involves reactivation of MEK–ERK MAP kinase signalling. Drug resistance due to overexpression of oncogenic BRAF-V600E leads to 'oncogene overdose' following cessation of drug administration — a phenomenon that could be clinically exploitable to forestall the onset of drug resistance.The efficacy of RAF inhibitors in tumours with other RAF mutations is mostly unknown, although preclinical studies indicate varied responses that are inhibitor-specific and depend on the biochemical mechanism of oncogene activation.