Affinage

BRAF

Serine/threonine-protein kinase B-raf · UniProt P15056

Round 2 corrected
Length
766 aa
Mass
84.4 kDa
Annotated
2026-04-28
130 papers in source corpus 22 papers cited in narrative 22 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BRAF is a RAS-regulated serine/threonine kinase that serves as the principal activator of the MEK–ERK MAPK cascade, governing cell proliferation, differentiation, senescence, and survival. Its kinase domain adopts an autoinhibited conformation in which the activation segment associates with the P-loop; oncogenic mutations—most commonly V600E—disrupt this interaction, yielding a constitutively active monomer that directly phosphorylates MEK, whereas kinase-impaired (class 3) mutants such as D594G signal allosterically through RAS-dependent BRAF–CRAF heterodimers (PMID:15035987, PMID:31929109). BRAF activity is further modulated by p300-mediated acetylation at K601 (reversed by SIRT1), which promotes RAF dimerization and drug resistance, and by copper availability through CTR1, which is required for productive MEK phosphorylation (PMID:35045286, PMID:24717435). Somatic BRAF mutations—found in ~66% of melanomas and many other cancers—drive tumorigenesis but also trigger oncogene-induced senescence in primary melanocytes; acquired resistance to BRAF inhibitors arises through NRAS mutation, PDGFRβ upregulation, COT/MAP3K8 expression, or FGF1–FGFR reactivation, while first-generation ATP-competitive RAF inhibitors paradoxically activate MAPK in RAS-mutant cells by promoting wild-type RAF dimerization (PMID:12068308, PMID:16079850, PMID:20130576, PMID:21107323).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2002 High

    The discovery that BRAF is the most frequently mutated kinase in melanoma established it as a direct oncogenic driver, with V600E accounting for ~80% of mutations and conferring constitutive kinase activity independent of RAS.

    Evidence Genome-wide cancer mutation screen, in vitro kinase assays, NIH3T3 transformation assay across hundreds of tumor samples

    PMID:12068308

    Open questions at the time
    • Structural basis of how V600E activates the kinase was unknown
    • Whether mutant BRAF could be therapeutically targeted was untested
  2. 2004 High

    Crystallography of the BRAF kinase domain revealed that the P-loop–activation segment interaction maintains autoinhibition and that oncogenic mutations disrupt this interaction; critically, kinase-impaired mutants were shown to activate ERK through CRAF rather than directly phosphorylating MEK, establishing two mechanistically distinct classes of BRAF oncogenic mutations.

    Evidence X-ray crystallography of WT and V599E BRAF kinase domains, in vitro kinase assays of 22 mutants, cellular ERK signaling assays

    PMID:15035987

    Open questions at the time
    • Precise mechanism by which kinase-dead BRAF activates CRAF (allosteric vs. transphosphorylation) was unresolved
    • No co-structure of BRAF dimers available
  3. 2005 High

    Demonstrating that BRAF(V600E) triggers oncogene-induced senescence rather than proliferation in primary melanocytes resolved the paradox of why BRAF mutations are found in benign nevi, establishing a tumor-suppressive barrier that must be overcome for melanoma progression.

    Evidence Retroviral V600E expression in human melanocytes, SA-β-Gal and p16(INK4a) staining, in vivo nevi analysis

    PMID:16079850

    Open questions at the time
    • Which cooperating lesions allow escape from OIS was not defined
    • Molecular effectors downstream of BRAF in the senescence program were incompletely mapped
  4. 2010 High

    Three concurrent studies resolved how RAF inhibitors paradoxically activate ERK in RAS-mutant cells (via drug-induced wild-type RAF dimerization), how kinase-dead BRAF cooperates with oncogenic RAS through CRAF activation in vivo, and how clinical resistance to vemurafenib arises through PDGFRβ upregulation or NRAS mutations—collectively defining the dimerization-dependent and bypass mechanisms that limit monotherapy efficacy.

    Evidence Cellular signaling across tumor line panels, co-immunoprecipitation, membrane fractionation, conditional mouse models (kinase-dead Braf + oncogenic Ras), patient biopsies, resistant subline derivation

    PMID:20130576 PMID:20141835 PMID:21107320 PMID:21107323

    Open questions at the time
    • Whether dimer-breaking compounds could overcome paradoxical activation was untested
    • Full landscape of resistance mechanisms in patients was incomplete
  5. 2011 Medium

    Identification of TSC22D1 as a critical effector of C/EBPβ in BRAF(V600E)-driven OIS provided the first molecular link between the BRAF-ERK pathway and the transcriptional senescence program in melanocytes.

    Evidence Gene expression profiling, shRNA knockdown and overexpression in human fibroblasts/melanocytes, SA-β-Gal and p15 assays

    PMID:21448135

    Open questions at the time
    • Whether TSC22D1 is required for OIS in vivo was not tested
    • Other senescence effectors downstream of BRAF were not systematically mapped
  6. 2014 High

    Showing that copper, via CTR1, is required for BRAF(V600E)-driven MEK phosphorylation and tumorigenesis introduced a metabolic cofactor dependency into the MAPK signaling model and provided a rationale for copper chelation as a therapeutic strategy.

    Evidence CTR1 knockout/knockdown, MEK1 Cu-binding mutants, rescue experiments, tumor xenograft and mouse models, Cu chelation

    PMID:24717435

    Open questions at the time
    • Direct structural evidence of Cu binding to MEK in the BRAF–MEK complex was lacking
    • Clinical utility of Cu chelation was not established
  7. 2015 High

    Discovery that BRAF(V600E) upregulates the ketogenic enzyme HMGCL, leading to acetoacetate accumulation that selectively enhances V600E–MEK1 binding, revealed an unexpected metabolic feed-forward loop specific to the oncogenic mutant.

    Evidence Metabolomics, co-immunoprecipitation of BRAF variants with MEK1, HMGCL knockdown/overexpression, xenograft models

    PMID:26145173

    Open questions at the time
    • Structural basis of acetoacetate-enhanced V600E–MEK1 binding was unknown
    • Relevance beyond melanoma not tested
  8. 2016 High

    Mapping BRAF(V600E)-driven invasion to ERK-dependent phosphorylation of cortactin (actin remodeling/invadopodia) and Exo70 (MMP secretion) extended the functional repertoire of oncogenic BRAF from proliferation and senescence to metastatic cell behavior.

    Evidence F-actin/cortactin imaging, matrix degradation assays, BRAF inhibitor treatment in murine models and patient biopsies

    PMID:27210749

    Open questions at the time
    • Whether these effectors are relevant in non-melanoma BRAF-driven cancers was not addressed
    • Direct ERK phosphorylation sites on cortactin and Exo70 were not fully mapped
  9. 2017 High

    In vivo demonstration that kinase-dead BRAF(D594A) initiates lung adenocarcinoma and that wild-type BRAF is required to buffer MAPK output—its loss causing lethal ERK hyperactivation—established that BRAF functions both as an allosteric activator and a homeostatic regulator of MAPK flux.

    Evidence Conditional knock-in mouse models with genetic Braf ablation and pharmacological MEK inhibition

    PMID:28783725

    Open questions at the time
    • Whether this buffering role applies in tissues other than lung was not tested
    • Mechanism by which wild-type BRAF limits CRAF output was not structurally resolved
  10. 2018 High

    Concurrent studies showed that oncogenic BRAF suppresses necroptosis by silencing RIPK3 and upregulates nuclear ERK5 transcriptional activity, broadening the downstream effector landscape beyond canonical ERK1/2; additionally, PLX8394 was shown to selectively disrupt BRAF-containing dimers without affecting CRAF homodimers, providing a pharmacological proof-of-concept for dimer-selective RAF inhibition.

    Evidence Genome-wide screen of 941 cancer cell lines for RIPK3 loss, BRAF/AXL inhibitor rescue of necroptosis; ERK5 subcellular fractionation and combined BRAF/MEK5 inhibition; PLX8394 dimer disruption biochemistry across RAF isoforms

    PMID:29483645 PMID:30157175 PMID:30559419

    Open questions at the time
    • Whether RIPK3 silencing is epigenetic or transcriptional was not determined
    • ERK5-specific transcriptional targets downstream of BRAF were not identified
    • PLX8394 clinical efficacy in dimer-driven tumors was untested
  11. 2019 Medium

    Three advances refined the mechanistic picture: BRAF inhibitors were shown to stabilize an intermediate kinase conformation that allosterically enhances RAS–RAF binding independently of dimerization; peptide-mediated disruption of the BRAF dimer interface triggered proteasomal degradation of both RAF and MEK, revealing a scaffolding function; and FGF1–FGFR autocrine reactivation was identified as an adaptive resistance mechanism to combined BRAF/MEK inhibition.

    Evidence Luciferase-based BRAF conformation biosensors in melanoma cells; in silico peptide design with in vitro kinase and protein stability assays; drug-resistant cell line generation with FGFR inhibition in PDX models

    PMID:31243962 PMID:31453322 PMID:31515463

    Open questions at the time
    • Allosteric RAS–RAF enhancement awaits structural resolution
    • Scaffolding function of RAF dimers not confirmed in vivo
    • Clinical validation of FGFR co-inhibition in BRAF-mutant patients was lacking
  12. 2020 Medium

    Molecular dynamics and biochemical studies of class 3 mutant BRAF(D594G) demonstrated that the mutation shifts αC-helix orientation toward the active state, increasing dimerization potential and priming allosteric CRAF activation while bypassing P-loop autoinhibition; separately, a cooperative dimer-selective BRAF inhibitor (PHI1) was developed using structural insights from ponatinib, defining a new pharmacological class.

    Evidence MD simulations, biochemical dimerization/P-loop phosphorylation assays; structural analysis and medicinal chemistry with cell-based ERK assays

    PMID:31929109 PMID:32873792

    Open questions at the time
    • No experimental structure of D594G dimer was obtained
    • PHI1 not tested in vivo or in clinical samples
  13. 2022 Medium

    Identification of p300-mediated acetylation at K601 (reversed by SIRT1) as a direct activating modification of BRAF that promotes dimerization with RAF/KSR1 and confers BRAF inhibitor resistance added a post-translational regulatory layer to the dimerization-dependent activation model and explained the oncogenic K601E mutation as an acetylation mimic.

    Evidence Acetylation assays, p300/SIRT1 co-immunoprecipitation, BRAF dimerization and drug resistance assays, K601E mutation analysis

    PMID:35045286

    Open questions at the time
    • In vivo relevance of K601 acetylation in tumor progression not tested
    • Whether other acetyltransferases contribute is unknown
    • Structural basis of acetylation-enhanced dimerization not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full structural basis of RAS-driven BRAF dimerization at the membrane, the determinants of tissue-specific responses to kinase-dead BRAF alleles, and whether dimer-selective or cooperative RAF inhibitors can achieve durable clinical responses without paradoxical activation.
  • No full-length BRAF structure in complex with RAS at the membrane
  • Tissue-specific determinants of kinase-dead BRAF oncogenicity are undefined
  • Clinical durability of next-generation RAF inhibitors remains untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016740 transferase activity 4 GO:0060090 molecular adaptor activity 3
Localization
GO:0005829 cytosol 3 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 10 R-HSA-1643685 Disease 7 R-HSA-1640170 Cell Cycle 2 R-HSA-5357801 Programmed Cell Death 2
Partners
ARAFCRAFEP300KRASKSR1MEK1MEK2SIRT1
Complex memberships
BRAF homodimerBRAF-CRAF heterodimerBRAF-KSR1 complexRAF-MEK-ERK signaling complex

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 BRAF somatic missense mutations occur in 66% of malignant melanomas and at lower frequency across many human cancers; all mutations are within the kinase domain, with V599E (V600E) accounting for ~80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. RAS function is not required for growth of cancer cell lines with the V600E mutation. Genome-wide sequencing screen, in vitro kinase assays, NIH3T3 transformation assay, cell line growth assays Nature High 12068308
2004 Crystal structures of wild-type and oncogenic V599E BRAF kinase domains reveal that the activation segment is held in an inactive conformation by association with the P-loop. Most oncogenic mutations disrupt this inhibitory interaction, converting BRAF to its active conformation. High-activity mutants signal to ERK by directly phosphorylating MEK, whereas kinase-impaired mutants stimulate MEK by activating endogenous C-RAF, possibly via allosteric or transphosphorylation mechanisms. X-ray crystallography of BRAF kinase domain (WT and V599E), in vitro kinase assays of 22 BRAF mutants, ERK signaling assays in cells Cell High 15035987
2005 BRAF(V600E) expression in primary human melanocytes induces cell cycle arrest with hallmarks of oncogene-induced senescence (OIS), including p16(INK4a) induction and senescence-associated beta-galactosidase activity. Congenital naevi are invariably positive for SA-beta-Gal in vivo, demonstrating that BRAF(V600E) drives senescence rather than proliferation in the benign lesion context. Retroviral expression of BRAF(V600E) in human melanocytes, SA-beta-Gal assay, p16(INK4a) immunostaining, in vivo nevi analysis Nature High 16079850
2010 ATP-competitive RAF inhibitors have two opposing mechanisms depending on cellular context: in BRAF(V600E) tumors they block MAPK signaling, but in KRAS-mutant or RAS/RAF wild-type tumors they activate the RAF-MEK-ERK pathway by inducing wild-type RAF dimerization, membrane localization, and interaction with RAS-GTP—events linked to conformational effects on the RAF kinase domain independent of kinase inhibition. Cellular signaling assays in multiple tumor cell lines and xenograft models, biochemical studies of RAF dimerization, membrane fractionation, co-immunoprecipitation Nature High 20130576
2010 Kinase-dead BRAF, when present with oncogenic RAS, drives MEK-ERK signaling and tumor progression through CRAF. BRAF-selective drugs promote RAS-dependent BRAF binding to CRAF and CRAF activation specifically when oncogenic RAS is present. Kinase-dead Braf and oncogenic Ras cooperate to induce melanoma in mice. Genetic mouse model (kinase-dead Braf + oncogenic Ras), CRAF co-immunoprecipitation, MEK-ERK phosphorylation assays, siRNA knockdown, mouse melanoma model Cell High 20141835
2014 Copper (Cu) is required for oncogenic BRAF(V600E) signaling and tumorigenesis. CTR1 (Cu transporter 1) deficiency or MEK1 mutations disrupting Cu binding decreased BRAF(V600E)-driven signaling and tumor growth. A MEK1-MEK5 chimera that phosphorylated ERK1/2 independently of Cu, or active ERK2, restored tumor growth in Ctr1-deficient cells. Cu chelators reduced BRAF(V600E)-driven tumor growth. CTR1 knockdown/knockout in mouse and human cells, MEK1 Cu-binding mutants, rescue experiments, tumor xenograft/mouse models, Cu chelation treatment Nature High 24717435
2015 Oncogenic BRAF V600E upregulates the ketogenic enzyme HMGCL through octamer transcription factor Oct-1, leading to increased intracellular acetoacetate. Acetoacetate selectively enhances binding of BRAF(V600E) but not wild-type BRAF to MEK1, promoting MEK-ERK signaling activation in a V600E-specific manner. HMGCL suppression specifically attenuates proliferation and tumor growth in BRAF(V600E)-expressing cells. Metabolomics, co-immunoprecipitation of BRAF(V600E)/BRAF-WT with MEK1, HMGCL knockdown/overexpression, Oct-1 transcription factor assays, xenograft tumor models Molecular cell High 26145173
2016 BRAF(V600E) drives melanoma cell invasion by inducing phosphorylation of cortactin and the exocyst subunit Exo70 through ERK, which regulates actin dynamics (F-actin and cortactin foci/invadopodia) and matrix metalloprotease secretion, respectively. BRAF(V600E) inhibition blocks invasion, decreases cortactin foci in murine melanoma models and patient biopsies, and downregulates invadopodia-related genes. F-actin/cortactin imaging, matrix degradation assays, ERK substrate phosphorylation analysis, BRAF(V600E) inhibitor treatment, murine model and patient biopsies, genome-wide expression analysis Cell reports High 27210749
2017 Kinase-inactive BRAF(D631A) (corresponding to human BRAF(D594A)) acts as an oncogenic initiating event in lung adenocarcinoma in vivo. Co-expression with Kras(G12V) enhances tumor initiation via Craf kinase activity. Wild-type Braf kinase is required to sustain these tumors; its ablation causes excessive MAPK signaling leading to oncogenic toxicity, which can be reversed by MEK inhibition. Loss of wild-type Braf also triggers transdifferentiation of club cells. Conditional knock-in mouse models, Cre-mediated activation, genetic Braf ablation, pharmacological MEK inhibition, histopathological analysis Nature High 28783725
2018 PLX8394 inhibits ERK signaling by specifically disrupting BRAF-containing dimers (BRAF homodimers and BRAF-CRAF heterodimers) but not CRAF homodimers or ARAF-containing dimers. Differences in the N-terminal portion of the kinase domain among RAF isoforms determine this differential vulnerability. PLX8394 selectively inhibits ERK signaling in tumors driven by dimeric BRAF mutants, including fusions, splice variants, and V600 monomers, but spares CRAF-homodimer-driven signaling in normal cells. Cell-based ERK signaling assays, selective dimer disruption biochemistry, comparisons across RAF isoforms, tumor cell line panels with varied BRAF mutations Nature medicine High 30559419
2019 BRAF inhibitors stabilize an intermediate, inactive kinase conformation of BRAF(V600E) that enhances binary RAS:RAF interactions independently of RAF dimerization in melanoma cells. This represents an allosteric effect of drug-driven intramolecular communication between the kinase and RAS-binding domains of mutated BRAF, which may promote paradoxical kinase activation and drug resistance. Luciferase-based BRAF conformation biosensors, RAS:RAF interaction assays, melanoma cell RAF dimerization studies, structurally diverse inhibitor panel Science advances Medium 31453322
2020 BRAF(D594G), a kinase-dead class 3 mutant, has higher dimerization potential than wild-type BRAF. Molecular dynamics simulations show the D594G substitution orients the αC-helix toward the IN position and extends the activation loop, shifting equilibrium toward the active dimeric conformation, priming BRAF(D594G) as an allosteric activator of CRAF. BRAF/CRAF heterodimers are the most thermodynamically stable RAF dimers. BRAF(D594G):CRAF heterodimers bypass autoinhibitory P-loop phosphorylation. Cell biology, biochemical dimerization assays, molecular dynamics simulations, P-loop phosphorylation assays The Journal of biological chemistry Medium 31929109
2020 Ponatinib inhibits BRAF monomers and dimers by binding to an allosteric site that stabilizes a distinct αC-helix conformation. Using structural insights from ponatinib, a BRAF inhibitor PHI1 was developed that selectively inhibits BRAF dimers, with enhanced inhibition of the second protomer when the first is occupied (positively cooperative dimer inhibition), defining a novel class of dimer-selective inhibitors. Structural analysis, cell-based BRAF dimer selectivity assays, medicinal chemistry/compound development, ERK signaling assays Nature communications Medium 32873792
2022 The acetyltransferase p300 activates BRAF kinase by promoting BRAF K601 acetylation, a process antagonized by the deacetylase SIRT1. K601 acetylation facilitates BRAF dimerization with RAF proteins and KSR1, promotes melanoma cell proliferation, and contributes to BRAF(V600E) inhibitor resistance. The oncogenic K601E mutation mimics K601 acetylation to augment BRAF kinase activity. Acetylation assays, p300/SIRT1 co-immunoprecipitation, BRAF dimerization assays, cell proliferation and drug resistance assays, K601E mutation analysis Cell reports Medium 35045286
2019 Peptide inhibitors targeting the BRAF dimer interface potently inhibit kinase activity of BRAF homo- and heterodimers, including oncogenic BRAF(G469A). Targeting the dimer interface leads to protein degradation of both RAF and MEK, revealing a novel scaffolding function of RAF in protecting large MAPK signaling complexes from proteasomal degradation. In silico peptide design, in vitro kinase assays on BRAF homo/heterodimers, protein stability assays, RAF/MEK degradation studies in cancer cells ACS chemical biology Medium 31243962
2011 TSC22D1 short transcript is upregulated >100-fold in BRAF(E600)-induced senescence in human fibroblasts and melanocytes, while the large TSC22D1 protein variant is suppressed by proteasomal degradation. Selective depletion of the short form, or overexpression of the large form, abrogates OIS and suppresses inflammatory factors and p15(INK4B). TSC22D1 is a critical effector of C/EBPβ in BRAF(V600E)-driven OIS. Gene expression profiling, shRNA knockdown, overexpression experiments, senescence assays (SA-beta-Gal, p16/p15 staining) in human fibroblasts and melanocytes The EMBO journal Medium 21448135
2018 Oncogenic BRAF and AXL drive loss of RIPK3 expression in cancer cells, leading to resistance to necroptosis. Inhibition of BRAF (or AXL) rescues RIPK3 expression and restores necroptosis sensitivity, placing BRAF as an oncogenic driver that suppresses the RIPK1-RIPK3-MLKL necroptosis pathway. Genome-wide bioinformatics screen of 941 cancer cell lines, BRAF/AXL inhibitor treatment, RIPK3 expression rescue assays, necroptosis sensitivity assays PLoS biology Medium 30157175
2006 BRAF(V600E) signaling through MEK1/2 upregulates ERK3/MAPK6 expression. ERK3 protein is unstable and rapidly degraded upon pharmacological BRAF inhibition. In melanoma cells, RNAi knockdown of BRAF or MEK inhibitor treatment reduces ERK3 levels, demonstrating ERK3 as a downstream transcriptional target of the BRAF-MEK axis. Conditionally active BRAF(V600E) expression system, microarray expression profiling, pharmacological BRAF/MEK inhibition, RNAi knockdown, protein stability assays International journal of oncology Medium 16964379
2018 ERK5 expression, phosphorylation, and nuclear localization are positively regulated by oncogenic BRAF(V600E). Both ERK5 kinase and transcriptional transactivator activities are enhanced by BRAF. Nuclear ERK5 is critical for cell proliferation in melanoma, and combined pharmacological inhibition of BRAF(V600E) and MEK5 is required to decrease nuclear ERK5 and achieve greater anti-tumor efficacy. ERK5 knockdown, pharmacological inhibition of BRAF(V600E)/MEK5/ERK5, subcellular fractionation/localization assays, colony formation, xenograft models Oncogene Medium 29483645
2010 Acquired resistance to PLX4032 (vemurafenib) in BRAF(V600E) melanoma develops through mutually exclusive PDGFRβ upregulation or NRAS mutations, but not through secondary mutations in BRAF(V600E). PDGFRβ-upregulated cells maintain low activated RAS and do not reactivate MAPK upon PLX4032 treatment, while NRAS-mutant resistant cells show significant MAPK reactivation and MEK inhibitor sensitivity. PLX4032-resistant subline derivation, patient biopsy analysis, PDGFRβ/NRAS knockdown and overexpression, MAPK pathway signaling assays, patient-derived short-term cultures Nature High 21107323
2010 MAP3K8 (COT/Tpl2) drives resistance to RAF inhibition in BRAF(V600E) melanoma by activating ERK through MEK-dependent mechanisms that do not require RAF signaling. COT expression is associated with de novo and acquired resistance in BRAF(V600E) cell lines and patient-derived relapsing tumor tissue. Kinase ORF expression screen (~600 kinases), patient biopsy analysis, MEK/ERK signaling assays, COT inhibition studies Nature High 21107320
2019 In response to dual BRAF/MEK inhibitor treatment, transcriptional upregulation of FGF1 results in autocrine activation of FGFR, which reactivates ERK as an adaptive resistance mechanism. FGFR inhibition overcomes resistance to dual BRAF/MEK inhibitors in cell lines and patient-derived xenograft models. Drug-resistant cell line generation, pharmacologic synthetic lethal screen, FGF1 expression analysis, FGFR inhibition rescue experiments, PDX models Clinical cancer research Medium 31515463

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Mutations of the BRAF gene in human cancer. Nature 8350 12068308
2004 Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 2296 15035987
2012 Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. The New England journal of medicine 2209 23020132
2006 KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer research 1813 16618717
2013 Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. The New England journal of medicine 1802 24024839
2010 Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 1754 21107323
2010 Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. The Lancet. Oncology 1728 20619739
2005 BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 1707 16079850
2017 Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer cell 1665 28810144
2014 Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. The New England journal of medicine 1652 25265494
2006 CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nature genetics 1558 16804544
2014 Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. The New England journal of medicine 1504 25265492
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. The New England journal of medicine 1411 26287849
2010 RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 1336 20130576
2006 A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nature biotechnology 1336 16964243
2002 High frequency of BRAF mutations in nevi. Nature genetics 1311 12447372
2008 Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1310 19001320
2003 High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer research 1269 12670889
2010 Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 1221 20141835
2015 High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities. Cell 1200 26627737
2010 COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 1193 21107320
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2002 Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 1032 12198537
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2009 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. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 956 20008640
2010 Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 902 20519626
2002 BRAF and RAS mutations in human lung cancer and melanoma. Cancer research 880 12460918
2011 Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 860 21343559
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. The Journal of clinical endocrinology and metabolism 816 14602780
2011 Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta neuropathologica 814 21274720
2011 BRAF mutations in hairy-cell leukemia. The New England journal of medicine 802 21663470
2012 The role of BRAF V600 mutation in melanoma. Journal of translational medicine 598 22554099
2015 Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma. Science translational medicine 481 25787767
2018 Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer. Cancer discovery 477 29431699
2014 Copper is required for oncogenic BRAF signalling and tumorigenesis. Nature 460 24717435
2018 BRAF Inhibition in BRAFV600-Mutant Gliomas: Results From the VE-BASKET Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 273 30351999
2014 Identification of recurrent SMO and BRAF mutations in ameloblastomas. Nature genetics 265 24859340
2020 Clinical Development of BRAF plus MEK Inhibitor Combinations. Trends in cancer 259 32540454
2014 Activating FGFR2-RAS-BRAF mutations in ameloblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research 216 24993163
2007 BRAF(E600) in benign and malignant human tumours. Oncogene 214 17724477
2016 Resistant mechanisms to BRAF inhibitors in melanoma. Annals of translational medicine 181 27429963
2006 BRAF and NRAS mutations in melanoma and melanocytic nevi. Melanoma research 181 16845322
2018 RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling. Nature medicine 159 30559419
2004 Microarray expression profiling in melanoma reveals a BRAF mutation signature. Oncogene 147 15048078
2015 Metabolic Rewiring by Oncogenic BRAF V600E Links Ketogenesis Pathway to BRAF-MEK1 Signaling. Molecular cell 133 26145173
2020 BRAF Inhibitors: Molecular Targeting and Immunomodulatory Actions. Cancers 127 32645969
2013 Clinicopathological relevance of BRAF mutations in human cancer. Pathology 126 23594689
2015 BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model. Proceedings of the National Academy of Sciences of the United States of America 115 25624498
2014 Overcoming resistance to BRAF inhibition in BRAF-mutated metastatic melanoma. Oncotarget 104 25344914
2011 Role of BRAF in thyroid oncogenesis. Clinical cancer research : an official journal of the American Association for Cancer Research 96 21900390
2013 To BRAF or not to BRAF: is that even a question anymore? Journal of neuropathology and experimental neurology 95 23242278
2017 Overcoming resistance to BRAF inhibitors. Annals of translational medicine 94 29114545
2015 Clinical detection and categorization of uncommon and concomitant mutations involving BRAF. BMC cancer 94 26498038
2017 A Braf kinase-inactive mutant induces lung adenocarcinoma. Nature 86 28783725
2006 BRAF somatic mutations in malignant melanoma and melanocytic naevi. Melanoma research 84 16567964
2013 B-Raf and the inhibitors: from bench to bedside. Journal of hematology & oncology 82 23617957
2005 Alterations of the BRAF gene in thyroid tumors. Endocrine pathology 82 16299399
2018 Current Insights of BRAF Inhibitors in Cancer. Journal of medicinal chemistry 81 29461827
2023 Precision oncology for BRAF-mutant cancers with BRAF and MEK inhibitors: from melanoma to tissue-agnostic therapy. ESMO open 77 36842301
2021 BRAF Gene and Melanoma: Back to the Future. International journal of molecular sciences 77 33801689
2013 Concomitant BRAF and PI3K/mTOR blockade is required for effective treatment of BRAF(V600E) colorectal cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 75 23549875
2018 BRAF and AXL oncogenes drive RIPK3 expression loss in cancer. PLoS biology 73 30157175
2014 Effects of BRAF mutations and BRAF inhibition on immune responses to melanoma. Molecular cancer therapeutics 72 25385327
2008 Clinical implications of BRAF mutation in thyroid carcinoma. Trends in endocrinology and metabolism: TEM 69 18337114
2022 BRAF mutations in thyroid cancer. Current opinion in oncology 67 34636352
2008 Therapeutic strategies for inhibiting oncogenic BRAF signaling. Current opinion in pharmacology 64 18644254
2020 Inhibitors of BRAF dimers using an allosteric site. Nature communications 63 32873792
2018 Combined BRAF and HSP90 Inhibition in Patients with Unresectable BRAF V600E-Mutant Melanoma. Clinical cancer research : an official journal of the American Association for Cancer Research 63 29674508
2019 Atypical BRAF and NRAS Mutations in Mucosal Melanoma. Cancers 61 31398831
2015 ENDOCRINE TUMORS: BRAF V600E mutations in papillary craniopharyngioma. European journal of endocrinology 60 26563980
2018 ERK5 is activated by oncogenic BRAF and promotes melanoma growth. Oncogene 58 29483645
2016 RAS and BRAF in metastatic colorectal cancer management. Journal of gastrointestinal oncology 58 27747083
2014 Alternative BRAF mutations in BRAF V600E-negative hairy cell leukaemias. British journal of haematology 58 24433452
2015 BRAF VE1 immunoreactivity patterns in epithelioid glioblastomas positive for BRAF V600E mutation. The American journal of surgical pathology 56 25581727
2020 A BRAF new world. Critical reviews in oncology/hematology 52 32485528
2021 BRAF, MEK and EGFR inhibition as treatment strategies in BRAF V600E metastatic colorectal cancer. Therapeutic advances in medical oncology 49 33747149
2020 BRAF inhibition protects against hearing loss in mice. Science advances 48 33268358
2016 Oncogenic BRAF-Mediated Melanoma Cell Invasion. Cell reports 46 27210749
2019 Development of Allosteric BRAF Peptide Inhibitors Targeting the Dimer Interface of BRAF. ACS chemical biology 45 31243962
2019 Adaptive Resistance to Dual BRAF/MEK Inhibition in BRAF-Driven Tumors through Autocrine FGFR Pathway Activation. Clinical cancer research : an official journal of the American Association for Cancer Research 44 31515463
2021 Targeting mTOR signaling overcomes acquired resistance to combined BRAF and MEK inhibition in BRAF-mutant melanoma. Oncogene 43 34304249
2012 Targeting oncogenic BRAF in human cancer. Current topics in microbiology and immunology 43 21818706
2020 BRAF mutation and its inhibitors in sarcoma treatment. Cancer medicine 41 32476297
2017 New somatic BRAF splicing mutation in Langerhans cell histiocytosis. Molecular cancer 41 28679432
2023 A reversible SRC-relayed COX2 inflammatory program drives resistance to BRAF and EGFR inhibition in BRAFV600E colorectal tumors. Nature cancer 40 36759733
2021 Targeting BRAF and RAS in Colorectal Cancer. Cancers 40 34063682
2016 BET and BRAF inhibitors act synergistically against BRAF-mutant melanoma. Cancer medicine 40 27169980
2022 Tissue-Agnostic Activity of BRAF plus MEK Inhibitor in BRAF V600-Mutant Tumors. Molecular cancer therapeutics 38 35413124
2021 BRAF Heterogeneity in Melanoma. Current treatment options in oncology 37 33558987
2012 Autoantibodies to PAD4 and BRAF in rheumatoid arthritis. Autoimmunity reviews 37 22349616
2020 Efficacy of BRAF-Inhibitor Therapy in BRAFV600E -Mutated Adult Langerhans Cell Histiocytosis. The oncologist 36 32985015
2016 Antitumor Activity of BRAF Inhibitor and IFNα Combination in BRAF-Mutant Melanoma. Journal of the National Cancer Institute 36 26851802
2019 Epigenetic Mechanisms of Escape from BRAF Oncogene Dependency. Cancers 34 31581557
2015 Survival advantage combining a BRAF inhibitor and radiation in BRAF V600E-mutant glioma. Journal of neuro-oncology 34 26384810
2007 Therapeutic strategies for targeting BRAF in human cancer. Reviews on recent clinical trials 34 18473997
2017 Dual EGFR and BRAF blockade overcomes resistance to vemurafenib in BRAF mutated thyroid carcinoma cells. Cancer cell international 32 29033690
2016 Combined BRAFV600E and MEK blockade for BRAFV600E-mutant gliomas. Journal of neuro-oncology 32 27848137
2007 Mouse models for BRAF-induced cancers. Biochemical Society transactions 32 17956344
2017 BRAF internal deletions and resistance to BRAF/MEK inhibitor therapy. Pigment cell & melanoma research 31 29171936
2015 The role of BRAF in the pathogenesis of thyroid carcinoma. Frontiers in bioscience (Landmark edition) 31 25961545
2011 Biological challenges of BRAF inhibitor therapy. Molecular oncology 31 21393075
2015 Comparative Aspects of BRAF Mutations in Canine Cancers. Veterinary sciences 30 29061943
2019 BRAF inhibitors promote intermediate BRAF(V600E) conformations and binary interactions with activated RAS. Science advances 29 31453322
2015 BRAF Immunohistochemistry Using Clone VE1 is Strongly Concordant with BRAF(V600E) Mutation Test in Papillary Thyroid Carcinoma. Endocrine pathology 29 25957797
2013 BRAF inhibitors: From the laboratory to clinical trials. Critical reviews in oncology/hematology 29 24388103
2020 Analyses of the oncogenic BRAFD594G variant reveal a kinase-independent function of BRAF in activating MAPK signaling. The Journal of biological chemistry 28 31929109
2018 The Role of Autophagy in the Resistance to BRAF Inhibition in BRAF-Mutated Melanoma. Targeted oncology 28 29667105
2017 The landscape of BRAF transcript and protein variants in human cancer. Molecular cancer 28 28454577
2017 Strategies for Overcoming Resistance in Tumours Harboring BRAF Mutations. International journal of molecular sciences 27 28282860
2016 Concomitant KIT/BRAF and PDGFRA/BRAF mutations are rare events in gastrointestinal stromal tumors. Oncotarget 27 27097112
2018 Inhibition of MERTK Promotes Suppression of Tumor Growth in BRAF Mutant and BRAF Wild-Type Melanoma. Molecular cancer therapeutics 26 30482852
2018 BRAF Mutations in Low-Grade Serous Ovarian Cancer and Response to BRAF Inhibition. JCO precision oncology 26 35135122
2012 MEK and RAF inhibitors for BRAF-mutated cancers. Expert reviews in molecular medicine 26 23058743
2011 Antagonistic TSC22D1 variants control BRAF(E600)-induced senescence. The EMBO journal 26 21448135
2021 Advances in anti-BRAF therapies for lung cancer. Investigational new drugs 25 33474634
2021 Autophagy Inhibition in BRAF-Driven Cancers. Cancers 24 34298710
2021 IGF1R/IR Mediates Resistance to BRAF and MEK Inhibitors in BRAF-Mutant Melanoma. Cancers 24 34831014
2018 Immunohistochemical analysis of BRAF V600E mutation in ameloblastomas. Clinical oral investigations 22 29855709
2006 Regulation of ERK3/MAPK6 expression by BRAF. International journal of oncology 22 16964379
2022 Acetylation-dependent regulation of BRAF oncogenic function. Cell reports 21 35045286
2015 BRAF and MEK inhibition for the treatment of advanced BRAF mutant melanoma. Expert opinion on pharmacotherapy 21 26001180
2008 BRAF kinase in melanoma development and progression. Expert reviews in molecular medicine 21 18279546
2005 Roles of RAS and BRAF mutations in thyroid carcinogenesis. Fukushima journal of medical science 21 16555627
2019 Mitochondrial metabolic reprograming via BRAF inhibition ameliorates senescence. Experimental gerontology 20 31421186
2014 BRAF Mutation in Hairy Cell Leukemia. Oncology reviews 20 25992240
2013 Dabrafenib for treatment of BRAF-mutant melanoma. Pharmacogenomics and personalized medicine 20 24516336