Genomes and Genes
proto oncogene proteins b raf
Summary: A raf kinase subclass found at high levels in neuronal tissue. The B-raf Kinases are MAP kinase kinase kinases that have specificity for MAP KINASE KINASE 1 and MAP KINASE KINASE 2.
- Tidyman W, Rauen K. Noonan, Costello and cardio-facio-cutaneous syndromes: dysregulation of the Ras-MAPK pathway. Expert Rev Mol Med. 2008;10:e37 pubmed publisher..Here we review the clinical consequences of the known molecular lesions associated with Noonan syndrome, Costello syndrome and cardio-facio-cutaneous syndrome, and explore possible therapeutic modalities for treatment. ..
- Beadling C, Jacobson Dunlop E, Hodi F, Le C, Warrick A, Patterson J, et al. KIT gene mutations and copy number in melanoma subtypes. Clin Cancer Res. 2008;14:6821-8 pubmed publisher..Screening for KIT mutations may open up new treatment options for melanoma patients. ..
- Sievert A, Jackson E, Gai X, Hakonarson H, Judkins A, Resnick A, et al. Duplication of 7q34 in pediatric low-grade astrocytomas detected by high-density single-nucleotide polymorphism-based genotype arrays results in a novel BRAF fusion gene. Brain Pathol. 2009;19:449-58 pubmed publisher..Further studies are required to determine the role of this fusion gene in downstream MAPK signaling and its role in development of pediatric low-grade astrocytomas. ..
- Platz A, Egyhazi S, Ringborg U, Hansson J. Human cutaneous melanoma; a review of NRAS and BRAF mutation frequencies in relation to histogenetic subclass and body site. Mol Oncol. 2008;1:395-405 pubmed publisher..Common alterations of the signal transducing network seem to represent molecular hallmarks of cutaneous melanomas and therefore should continue to strongly stimulate design and testing of targeted molecular interventions. ..
- Siena S, Sartore Bianchi A, Di Nicolantonio F, Balfour J, Bardelli A. Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer. J Natl Cancer Inst. 2009;101:1308-24 pubmed publisher..The use of KRAS mutations as a selection biomarker for anti-EGFR monoclonal antibody (eg, panitumumab or cetuximab) treatment is the first major step toward individualized treatment for patients with metastatic colorectal cancer. ..
- Zheng B, Jeong J, Asara J, Yuan Y, Granter S, Chin L, et al. Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol Cell. 2009;33:237-47 pubmed publisher..Our findings provide a molecular linkage between the LKB1-AMPK and the RAF-MEK-ERK pathways and suggest that suppression of LKB1 function by B-RAF V600E plays an important role in B-RAF V600E-driven tumorigenesis. ..
- Smalley K, Flaherty K. Integrating BRAF/MEK inhibitors into combination therapy for melanoma. Br J Cancer. 2009;100:431-5 pubmed publisher..In the current review, we discuss other pathways likely to be important for melanoma progression and suggest possible drug combinations for future clinical testing. ..
- Flaherty K, Puzanov I, Kim K, Ribas A, McArthur G, Sosman J, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809-19 pubmed publisher..Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients. (Funded by Plexxikon and Roche Pharmaceuticals.) ..
- Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, Santini D, et al. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer. 2009;101:715-21 pubmed publisher..0005) and PFS (HR: 0.51, P=0.006) compared with KRAS and BRAF wild-type patients. Assessing KRAS codons 61/146 and BRAF V600E mutations might help optimising the selection of the candidate patients to receive anti-EGFR moAbs. ..
- Bosman F, Yan P, Tejpar S, Fiocca R, Van Cutsem E, Kennedy R, et al. Tissue biomarker development in a multicentre trial context: a feasibility study on the PETACC3 stage II and III colon cancer adjuvant treatment trial. Clin Cancer Res. 2009;15:5528-33 pubmed publisher..Our results support the notion that as a rule, translational studies based on FFPE should be included in prospective clinical trials. ..
- Zlobec I, Molinari F, Kovac M, Bihl M, Altermatt H, Diebold J, et al. Prognostic and predictive value of TOPK stratified by KRAS and BRAF gene alterations in sporadic, hereditary and metastatic colorectal cancer patients. Br J Cancer. 2010;102:151-61 pubmed publisher..The inhibition of TOPK, which could benefit 30-40% of CRC patients, may represent a new avenue of investigation for targeted therapy. ..
- Rajakulendran T, Sahmi M, Lefrancois M, Sicheri F, Therrien M. A dimerization-dependent mechanism drives RAF catalytic activation. Nature. 2009;461:542-5 pubmed publisher..Together, our data identify the side-to-side dimer interface of RAF as a potential therapeutic target for intervention in BRAF-dependent tumorigenesis. ..
- Fratev F, Jónsdóttir S, Mihaylova E, Pajeva I. Molecular basis of inactive B-RAF(WT) and B-RAF(V600E) ligand inhibition, selectivity and conformational stability: an in silico study. Mol Pharm. 2009;6:144-57 pubmed publisher..Overall data revealed the important role of Lys601 for ligand activity, selectivity and protein stabilization, proposing an explanation of the observed strong kinase activation in the K601E mutated form. ..
- Ogino S, Nosho K, Kirkner G, Shima K, Irahara N, Kure S, et al. PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. J Clin Oncol. 2009;27:1477-84 pubmed publisher..The adverse effect of PIK3CA mutation may be potentially limited to patients with KRAS wild-type tumors. ..
- Richman S, Seymour M, Chambers P, Elliott F, Daly C, Meade A, et al. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol. 2009;27:5931-7 pubmed publisher..There is no evidence that patients with KRAS/BRAF mutated tumors are less likely to benefit from these standard chemotherapy agents. ..
- Di Nicolantonio F, Martini M, Molinari F, Sartore Bianchi A, Arena S, Saletti P, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;26:5705-12 pubmed publisher..Double-hit therapies aimed at simultaneous inhibition of epidermal growth factor receptor and BRAF warrant exploration in CRC patients carrying the V600E oncogenic mutation. ..
- Jones D, Kocialkowski S, Liu L, Pearson D, Bäcklund L, Ichimura K, et al. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008;68:8673-7 pubmed publisher..This is the first report of BRAF activation through rearrangement as a frequent feature in a sporadic tumor. The frequency and specificity of this change underline its potential both as a therapeutic target and as a diagnostic tool. ..
- Hoeflich K, Herter S, Tien J, Wong L, Berry L, Chan J, et al. Antitumor efficacy of the novel RAF inhibitor GDC-0879 is predicted by BRAFV600E mutational status and sustained extracellular signal-regulated kinase/mitogen-activated protein kinase pathway suppression. Cancer Res. 2009;69:3042-51 pubmed publisher..Taken together, these studies increase our understanding of the molecular determinants for antitumor efficacy resulting from RAF pathway inhibition and have implications for therapeutic intervention in the clinic. ..
- Hinoue T, Weisenberger D, Pan F, Campan M, Kim M, Young J, et al. Analysis of the association between CIMP and BRAF in colorectal cancer by DNA methylation profiling. PLoS ONE. 2009;4:e8357 pubmed publisher..Our data will be useful for future investigations toward understanding CIMP in colorectal cancer and gaining insights into the role of aberrant DNA hypermethylation in colorectal tumorigenesis. ..
- Dhomen N, Reis Filho J, da Rocha Dias S, Hayward R, Savage K, Delmas V, et al. Oncogenic Braf induces melanocyte senescence and melanoma in mice. Cancer Cell. 2009;15:294-303 pubmed publisher..Thus, we have developed a mouse model of melanoma driven by Braf(V600E) expressed at physiological levels that reflects the genetics and pathology of the human disease...
- Sartore Bianchi A, Di Nicolantonio F, Nichelatti M, Molinari F, De Dosso S, Saletti P, et al. Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer. PLoS ONE. 2009;4:e7287 pubmed publisher..Comprehensive molecular dissection of the EGFR signaling pathways should be considered to select mCRC patients for cetuximab- or panitumumab-based therapies. ..
- Dhomen N, Marais R. BRAF signaling and targeted therapies in melanoma. Hematol Oncol Clin North Am. 2009;23:529-45, ix pubmed publisher..The authors discuss what they learned from clinical trials using first- and second-generation inhibitors to this pathway. ..
- Ménard D, Niculescu Duvaz I, Dijkstra H, Niculescu Duvaz D, Suijkerbuijk B, Zambon A, et al. Novel potent BRAF inhibitors: toward 1 nM compounds through optimization of the central phenyl ring. J Med Chem. 2009;52:3881-91 pubmed publisher..Substitution on the central phenyl ring of a 3-fluoro, a naphthyl, or a 3-thiomethyl group improves activity to yield compounds with an IC(50) of 1 nM for purified (V600E)BRAF and nanomolar activity in cells. ..
- Laurent Puig P, Cayre A, Manceau G, Buc E, Bachet J, Lecomte T, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol. 2009;27:5924-30 pubmed publisher..Subsequent studies in clinical trial cohorts will be required to confirm the clinical utility of these markers. ..
- Roth A, Tejpar S, Delorenzi M, Yan P, Fiocca R, Klingbiel D, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol. 2010;28:466-74 pubmed publisher..2; 95% CI, 1.4 to 3.4; P = .0003). In stage II-III colon cancer, the KRAS mutation status does not have major prognostic value. BRAF is prognostic for OS in MS-L/S tumors. ..
- Halaban R, Zhang W, Bacchiocchi A, Cheng E, Parisi F, Ariyan S, et al. PLX4032, a selective BRAF(V600E) kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF melanoma cells. Pigment Cell Melanoma Res. 2010;23:190-200 pubmed publisher..The results suggest that the drug can confer an advantage to BRAF(WT) primary and metastatic tumor cells in vivo and provide markers for monitoring clinical responses. ..
- Niculescu Duvaz D, Gaulon C, Dijkstra H, Niculescu Duvaz I, Zambon A, Ménard D, et al. Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF). J Med Chem. 2009;52:2255-64 pubmed publisher..These compounds have great potential in the treatment of mutant BRAF melanomas. ..
- Søndergaard J, Nazarian R, Wang Q, Guo D, Hsueh T, Mok S, et al. Differential sensitivity of melanoma cell lines with BRAFV600E mutation to the specific Raf inhibitor PLX4032. J Transl Med. 2010;8:39 pubmed publisher..In conclusion, BRAFV600E mutant melanoma cell lines displayed a range of sensitivities to PLX4032 and metabolic imaging using PET probes can be used to assess sensitivity. ..
- Lugli A, Karamitopoulou E, Panayiotides I, Karakitsos P, Rallis G, Peros G, et al. CD8+ lymphocytes/ tumour-budding index: an independent prognostic factor representing a 'pro-/anti-tumour' approach to tumour host interaction in colorectal cancer. Br J Cancer. 2009;101:1382-92 pubmed publisher..009) and treated patients (P<0.001). The CD8+ lymphocyte : tumour-budding index is an independent prognostic factor in colorectal cancer and a promising approach for a future prognostic score for patients with this disease. ..
- Smalley K, Nathanson K, Flaherty K. Genetic subgrouping of melanoma reveals new opportunities for targeted therapy. Cancer Res. 2009;69:3241-4 pubmed publisher..In the current review, we discuss how knowledge about these new melanoma subgroups may lead to improved strategies for treating melanomas harboring BRAF V600E mutations. ..
- Esteve Puig R, Canals F, Colome N, Merlino G, Recio J. Uncoupling of the LKB1-AMPKalpha energy sensor pathway by growth factors and oncogenic BRAF. PLoS ONE. 2009;4:e4771 pubmed publisher..Importantly, this mechanism reveals a new level for therapeutical intervention particularly relevant in tumors harboring a deregulated RAS-Erk1/2 pathway. ..
- Pratilas C, Taylor B, Ye Q, Viale A, Sander C, Solit D, et al. (V600E)BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proc Natl Acad Sci U S A. 2009;106:4519-24 pubmed publisher..Physiologic feedback inhibition of RAF/MEK signaling down-regulates ERK output in RTK cells; evasion of this feedback in mutant BRAF cells is associated with increased transcriptional output and MEK/ERK-dependent transformation. ..
- Rubinstein J, Sznol M, Pavlick A, Ariyan S, Cheng E, Bacchiocchi A, et al. Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. J Transl Med. 2010;8:67 pubmed publisher..Here we present evidence that a patient bearing the BRAF V600K mutation responded remarkably to PLX4032, suggesting that clinical trials should include all patients with activating BRAF V600E/K mutations. ..
- Nosho K, Kawasaki T, Chan A, Ohnishi M, Suemoto Y, Kirkner G, et al. Cyclin D1 is frequently overexpressed in microsatellite unstable colorectal cancer, independent of CpG island methylator phenotype. Histopathology. 2008;53:588-98 pubmed publisher..008). Cyclin D1 activation is associated with MSI and inversely with p21 loss in colorectal cancers. Cyclin D1 may play an important role in the development of MSI-high tumours, independent of CIMP status. ..
- Forshew T, Tatevossian R, Lawson A, Ma J, Neale G, Ogunkolade B, et al. Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas. J Pathol. 2009;218:172-81 pubmed publisher..Further fusions and activating mutations in BRAF were identified in 28% of grade II astrocytomas, highlighting the importance of the ERK/MAP kinase pathway in the development of paediatric low-grade gliomas. ..
- Barault L, Charon Barra C, Jooste V, de la Vega M, Martin L, Roignot P, et al. Hypermethylator phenotype in sporadic colon cancer: study on a population-based series of 582 cases. Cancer Res. 2008;68:8541-6 pubmed publisher..Our results show the interest of defining three subgroups of patients according to their methylation status (No-CIMP/CIMP-Low/CIMP-High). Methylation is an independent prognostic factor in MSS colon cancer. ..
- Hansen J, Grina J, Newhouse B, Welch M, Topalov G, Littman N, et al. Potent and selective pyrazole-based inhibitors of B-Raf kinase. Bioorg Med Chem Lett. 2008;18:4692-5 pubmed publisher..These inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. A subset of these inhibitors has demonstrated the ability to inhibit downstream ERK phosphorylation in LOX tumors from mouse xenograft studies. ..
- Bar E, Lin A, Tihan T, Burger P, Eberhart C. Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. J Neuropathol Exp Neurol. 2008;67:878-87 pubmed publisher..These data indicate that focal gains at chromosome 7q34 and increased BRAF-MEK-ERK signaling are common findings in sporadic pilocytic astrocytomas. ..
- Cartlidge R, Thomas G, Cagnol S, Jong K, Molton S, Finch A, et al. Oncogenic BRAF(V600E) inhibits BIM expression to promote melanoma cell survival. Pigment Cell Melanoma Res. 2008;21:534-44 pubmed publisher..These data suggest that regulation of BIM expression by BRAF-->MEK-->ERK signaling is one mechanism by which oncogenic BRAF(V600E) can influence the aberrant physiology of melanoma cells. ..
- Smalley K, Xiao M, Villanueva J, Nguyen T, Flaherty K, Letrero R, et al. CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations. Oncogene. 2009;28:85-94 pubmed publisher..In summary, we have identified a group of melanomas with low-activity BRAF mutations that are reliant upon CRAF-mediated survival activity. ..
- Takle A, Bamford M, Davies S, Davis R, Dean D, Gaiba A, et al. The identification of potent, selective and CNS penetrant furan-based inhibitors of B-Raf kinase. Bioorg Med Chem Lett. 2008;18:4373-6 pubmed publisher..One such compound, SB-699393 (17), was examined in vivo to challenge the hypothesis that selective B-Raf inhibitors may be of value in the treatment of stroke. ..
- Elisei R, Ugolini C, Viola D, Lupi C, Biagini A, Giannini R, et al. BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study. J Clin Endocrinol Metab. 2008;93:3943-9 pubmed publisher..In particular, the BRAF(V600E) mutation was demonstrated to be a poor prognostic factor independent from other clinicopathological features. ..
- Sweeney C, Boucher K, Samowitz W, Wolff R, Albertsen H, Curtin K, et al. Oncogenetic tree model of somatic mutations and DNA methylation in colon tumors. Genes Chromosomes Cancer. 2009;48:1-9 pubmed publisher..The oncogenetic tree model assumptions are appropriate for the observed heterogeneity of colon tumors, and the model produces a useful visual schematic of the sequence of events in pathways of colon carcinogenesis. ..
- Ogino S, Nosho K, Kirkner G, Kawasaki T, Meyerhardt J, Loda M, et al. CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut. 2009;58:90-6 pubmed publisher..KRAS mutation was unrelated to prognostic significance. CIMP-high appears to be an independent predictor of a low colon cancer-specific mortality, while BRAF mutation is associated with a high colon cancer-specific mortality. ..
- Montagut C, Sharma S, Shioda T, McDermott U, Ulman M, Ulkus L, et al. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res. 2008;68:4853-61 pubmed publisher..Geldanamycin effectively promotes the degradation of CRAF, thereby revealing a potential therapeutic strategy to overcome resistance to RAF inhibition in a subset of BRAF mutant tumors. ..
- Nosho K, Kawasaki T, Ohnishi M, Suemoto Y, Kirkner G, Zepf D, et al. PIK3CA mutation in colorectal cancer: relationship with genetic and epigenetic alterations. Neoplasia. 2008;10:534-41 pubmed..In addition, Pyrosequencing is useful in detecting PIK3CA mutation in archival paraffin tumor tissue. PIK3CA mutational data further emphasize heterogeneity of colorectal cancer at the molecular level. ..