Mutations in the<unk> gene can cause disease in two ways. First, mutations can be inherited and cause birth defects. Second, mutations can appear later in life and cause cancer, as an oncogene. Inherited mutations in this gene cause cardiofaciocutaneous syndrome, a disease characterized by heart defects, mental retardation and a distinctive facial appearance. Mutations in this gene have been found in cancers, including non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, papillary thyroid carcinoma, non-small-cell lung carcinoma, adenocarcinoma of the lung, brain tumors including glioblastoma and pleomorphic xanthoastrocytoma as well as inflammatory diseases like Erdheim-Chester disease. The V600E mutation of the<unk> gene has been associated with hairy cell leukemia in numerous studies and has been suggested for use in screening for Lynch syndrome to reduce the number of patients undergoing unnecessary MLH1 sequencing. Mutants More than 30 mutations of the<unk> gene associated with human cancers have been identified. The frequency of<unk> mutations varies widely in human cancers, from more than 80% in melanomas and nevi, to as little as 0–18% in other tumors, such as 1–3% in lung cancers and 5% in colorectal cancer. In 90% of the cases, thymine is substituted with adenine at nucleotide 1799. This leads to valine (V) being substituted for by glutamate (E) at codon 600 (now referred to as V600E) in the activation segment that has been found in human cancers. This mutation has been widely observed in papillary thyroid carcinoma, colorectal cancer, melanoma and non-small-cell lung cancer.<unk> V600E mutation are present in 57% of Langerhans cell histiocytosis patients. The V600E mutation is a likely driver mutation in 100% of cases of hairy cell leukaemia. High frequency of<unk> V600E mutations have been detected in ameloblastoma, a benign but locally infiltrative odontogenic neoplasm. The V600E mutation may also be linked, as a single-driver mutation (a genetic 'smoking gun') to certain cases of papillary craniopharyngioma development. Other mutations which have been found are R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, V600K, A727V, etc. and most of these mutations are clustered to two regions: the glycine-rich P loop of the N lobe and the activation segment and flanking regions. These mutations change the activation segment from inactive state to active state, for example in the previous cited paper it has been reported that the aliphatic side chain of Val599 interacts with the phenyl ring of Phe467 in the P loop. Replacing the medium-sized hydrophobic Val side chain with a larger and charged residue as found in human cancer(Glu, Asp, Lys, or Arg) would be expected to destabilize the interactions that maintain the DFG motif in an inactive conformation, so flipping the activation segment into the active position. Depending on the type of mutation the kinase activity towards MEK may also vary. Most of the mutants stimulate enhanced<unk> kinase activity toward MEK. However, a few mutants act through a different mechanism because although their activity toward MEK is reduced, they adopt a conformation that activates wild-type C-RAF, which then signals to ERK.<unk> V600E *<unk> V600E is a determinant of sensitivity to proteasome inhibitors. Vulnerability to proteasome inhibitors is dependent on persistent<unk> signaling, because<unk> V600E blockade by PLX4720 reversed sensitivity to carfilzomib in<unk> mutant colorectal cancer cells. Proteasome inhibition might represent a valuable targeting strategy in<unk> V600E-mutant colorectal tumors.<unk> inhibitors As mentioned above, some pharmaceutical firms are developing specific inhibitors of mutated<unk> protein for anticancer use because<unk> is a well-understood, high yield target. Vemurafenib (RG7204 or PLX4032) was licensed by the US Food and Drug Administration as Zelboraf for the treatment of metastatic melanoma in August 2011 based on Phase III clinical data. Improved survival was seen, as well as a response rate to treatment of 53%, compared to from 7-12% with the former best chemotherapeutic treatment, dacarbazine. In clinical trials,<unk> increased metastatic melanoma patient chance of survival. In spite of the drug's high efficacy, 20% of tumors still develop resistance to the treatment. In mice, 20% of tumors become resistant after 56 days. While the mechanisms of this resistance are still disputed, some hypotheses include the overexpression of<unk> to compensate for high concentrations of Vemurafenib and upstream upregulation of growth signaling. More general<unk> inhibitors include GDC-0879, PLX-4720, Sorafenib, dabrafenib and LGX818
BRAF 
KRAS
ABL 
TFM-4AS-1
Kras
P73
HERG
CoWIN