Affinage

BRAF

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

Length
766 aa
Mass
84.4 kDa
Annotated
2026-06-09
100 papers in source corpus 19 papers cited in narrative 19 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BRAF is a RAS-regulated serine/threonine kinase that functions as a core node of the MAPK (RAS-RAF-MEK-ERK) cascade and is a major oncogenic driver, most prominently through the recurrent V600E mutation that elevates kinase activity, transforms cells, and signals constitutively without requiring upstream RAS function (PMID:12068308). BRAF-mutant tumors across lineages are exquisitely dependent on downstream MEK, such that MEK inhibition arrests proliferation via cyclin D1 downregulation and G1 arrest (PMID:16273091), and the same dependence drives MAPK activation in diverse tumor contexts including ameloblastoma (PMID:24993163). The oncogenic output of BRAF V600E extends beyond proliferation: ERK-mediated phosphorylation of cortactin and the exocyst subunit Exo70 reprograms actin dynamics and matrix metalloprotease secretion to drive invasion (PMID:27210749), an ETS1-dependent axis sustains TERT promoter activity (PMID:31391125), and a mutation-specific metabolic loop in which Oct-1 drives HMGCL expression and acetoacetate selectively enhances V600E-MEK1 binding amplifies signaling (PMID:26145173). BRAF activity is negatively regulated by AMPK phosphorylation at Ser729, which promotes 14-3-3 association, disrupts KSR1 scaffolding, and attenuates MEK-ERK signaling (PMID:24095280). Distinct oncogenic mechanisms operate for non-V600 alterations: kinase-inactive BRAF can initiate tumorigenesis through CRAF, with wild-type BRAF kinase paradoxically required to restrain excessive MAPK output (PMID:28783725), and RAS-binding-domain deletions, splice insertions, and fusions activate signaling as RAF dimers that resist V600-monomer inhibitors but are blocked by dimer-disrupting agents (PMID:29171936, PMID:28679432, PMID:30559419). Structural work defines the basis for monomer- versus dimer-selective inhibition, including an allosteric αC-helix site supporting positive cooperativity within the dimer (PMID:32873792) and inhibitor-stabilized inactive conformations that enhance RAS:BRAF binding (PMID:31453322). Adaptive and acquired resistance to pathway inhibition arises through autocrine FGF1-FGFR reactivation of ERK (PMID:31515463) and an ERK-independent SRC-β-catenin axis sustained by a COX2/prostaglandin E2 loop (PMID:36759733).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2002 High

    Established that BRAF is a frequently mutated oncogenic kinase whose activating mutations render it constitutively active and independent of upstream RAS, defining it as a direct cancer driver rather than a passive relay.

    Evidence Genome-wide cancer sequencing with in vitro kinase assays, NIH3T3 transformation, and RAS-independence growth studies in melanoma

    PMID:12068308

    Open questions at the time
    • Did not resolve how different mutation classes signal (monomer vs dimer)
    • No structural basis for elevated kinase activity
  2. 2005 High

    Showed that BRAF mutation creates a lineage-independent therapeutic dependence on MEK, framing BRAF-mutant tumors as targetable through the downstream MAPK module.

    Evidence MEK inhibitor treatment of cell lines and xenografts stratified by BRAF/RAS status, with cyclin D1 and cell-cycle readouts

    PMID:16273091

    Open questions at the time
    • Did not address acquired resistance
    • MEK dependence shown but BRAF-direct inhibition strategy not yet defined
  3. 2013 High

    Identified a physiological brake on BRAF: AMPK phosphorylation at Ser729 reroutes BRAF away from KSR1 scaffolding toward 14-3-3, attenuating MAPK output and constraining BRAF-inhibitor-induced ERK hyperactivation.

    Evidence In vitro AMPK kinase assay, reciprocal co-IP of 14-3-3 and KSR1, site mutagenesis, and a mouse epidermal hyperplasia model

    PMID:24095280

    Open questions at the time
    • Relevance of Ser729 regulation in tumors with constitutive V600E unclear
    • How AMPK status modulates inhibitor response in patients not established
  4. 2015 High

    Revealed a mutation-specific metabolic feed-forward loop in which BRAF V600E induces ketogenic HMGCL via Oct-1, and the resulting acetoacetate selectively strengthens V600E-MEK1 binding to amplify signaling.

    Evidence Co-IP of V600E-MEK1 with/without acetoacetate, HMGCL shRNA, metabolite measurement, and xenograft growth

    PMID:26145173

    Open questions at the time
    • Structural basis for acetoacetate-enhanced binding not resolved
    • Generalizability to non-melanoma V600E tumors untested
  5. 2016 Medium

    Connected BRAF V600E signaling to the invasive phenotype by showing ERK-driven phosphorylation of cortactin and Exo70 controls actin dynamics and MMP secretion.

    Evidence F-actin/cortactin foci and ECM degradation assays, phospho-protein analysis, BRAF inhibition, murine model and patient biopsies

    PMID:27210749

    Open questions at the time
    • Single lab
    • Direct kinase-substrate relationship of ERK to Exo70/cortactin inferred from phospho-readouts
  6. 2017 High

    Demonstrated that kinase-inactive BRAF can initiate tumorigenesis through CRAF and that wild-type BRAF kinase paradoxically restrains MAPK signaling, exposing dimer- and isoform-dependent complexity in BRAF oncogenesis.

    Evidence Conditional knock-in mouse genetics with allele combinations, CRAF-activity epistasis, and MEK-inhibitor rescue

    PMID:28783725

    Open questions at the time
    • Molecular mechanism of wild-type BRAF restraining MAPK not fully defined
    • Human relevance of D594A-class mutants in this model untested
  7. 2017 Medium

    Characterized RAS-binding-domain-removing alterations — internal deletions and splice insertions — as dimer-driven signaling mechanisms underlying targeted-therapy resistance.

    Evidence Pre/post-treatment tumor sequencing for deletions; HEK293 expression and inhibitor (vemurafenib vs PLX8394) testing of an LCH splice insertion

    PMID:28679432 PMID:29171936

    Open questions at the time
    • Deletion constructs not functionally reconstituted
    • Limited mechanistic detail on dimer interface for these variants
  8. 2017 Medium

    Established that BRAF is expressed as multiple C-terminal isoforms whose abundance is post-translationally controlled, with BRAF-X2 selectively degraded by the proteasome.

    Evidence RNA-seq across cancer patients, isoform-specific protein detection, proteasome inhibition, and functional isoform assays

    PMID:28454577

    Open questions at the time
    • Ligase mediating BRAF-X2 degradation unidentified
    • Functional consequence of isoform balance in tumors unclear
  9. 2018 High

    Provided the mechanistic basis for dimer-selective RAF inhibition, showing PLX8394 disrupts BRAF-containing dimers via N-lobe sequence differences while sparing other RAF dimers, broadening the targetable mutant spectrum.

    Evidence Cell-based signaling and dimer disruption assays, RAF isoform structure-activity and mutagenesis, diverse BRAF-variant cell panels

    PMID:30559419

    Open questions at the time
    • In vivo efficacy across variant classes not fully mapped
    • Resistance to dimer-selective inhibitors not addressed
  10. 2019 Medium

    Defined structural and allosteric determinants of inhibitor action: a αC-helix allosteric site supporting intra-dimer positive cooperativity, and inhibitor-stabilized inactive conformations that enhance RAS:BRAF binding to promote paradoxical activation.

    Evidence Structural binding and αC-helix conformation analysis with PHI1 development (2020); luciferase conformation biosensors and RAS:RAF binary interaction assays in melanoma cells (2019)

    PMID:31453322 PMID:32873792

    Open questions at the time
    • Biosensor-based allosteric communication is partly inferred
    • Single-lab structural models await orthogonal confirmation
  11. 2019 Medium

    Identified adaptive resistance routes that reactivate ERK or bypass it: autocrine FGF1-FGFR signaling restores ERK under BRAF/MEK inhibition.

    Evidence Resistant line generation, synthetic-lethal screen, FGF1 transcriptional analysis, FGFR inhibitor rescue in cells and PDX

    PMID:31515463

    Open questions at the time
    • Single lab
    • Transcriptional driver of FGF1 upregulation not defined
  12. 2023 Medium

    Extended the resistance landscape beyond ERK by showing SRC activation, driven by a COX2/PGE2 autocrine loop, reprograms transcription via β-catenin to sustain BRAF-mutant colorectal cancer under targeted therapy.

    Evidence Kinase activity mapping, β-catenin reporter, COX2/PGE2 analysis, and PDX combination treatment

    PMID:36759733

    Open questions at the time
    • Single lab
    • Mechanism coupling SRC to COX2 induction not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the regulatory inputs (AMPK/14-3-3, metabolite loops, isoform balance) integrate with the diverse oncogenic signaling modes (monomer, dimer, kinase-dead/CRAF) to determine inhibitor response and resistance in vivo remains incompletely defined.
  • No unified structural model linking conformation, dimerization, and RAS binding across mutant classes
  • Predictive markers distinguishing FGFR- vs SRC- vs RBD-deletion resistance lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0016740 transferase activity 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3
Partners
14-3-3CRAFKSR1MEK1

Evidence

Reading pass · 19 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, predominantly within the kinase domain; mutated BRAF proteins (including V599E/V600E) 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, establishing BRAF as a constitutively active, RAS-independent oncogenic kinase. Genome-wide sequencing of cancer samples, in vitro kinase activity assays, NIH3T3 transformation assays, cancer cell line growth studies Nature High 12068308
2005 BRAF mutation (V600E) confers selective sensitivity to MEK inhibition regardless of tissue lineage; pharmacological MEK inhibition completely abrogated tumor growth in BRAF-mutant xenografts, correlating with downregulation of cyclin D1 and G1 arrest, establishing BRAF-mutant tumors as exquisitely MEK-dependent. Small-molecule MEK inhibitor treatment of cell lines and xenografts stratified by BRAF/RAS mutation status; cyclin D1 expression analysis; cell-cycle analysis Nature High 16273091
2013 BRAF is phosphorylated at Ser729 by AMP-activated protein kinase (AMPK); this phosphorylation promotes association of BRAF with 14-3-3 proteins and disrupts its interaction with the KSR1 scaffolding protein, leading to attenuation of MEK-ERK signaling, impaired keratinocyte proliferation, and suppression of BRAF inhibitor-induced ERK hyperactivation. In vitro kinase assay (AMPK phosphorylation of BRAF), co-immunoprecipitation (BRAF–14-3-3 and BRAF–KSR1 interactions), site-specific mutagenesis, cell-cycle analysis, mouse skin epidermal hyperplasia model Molecular Cell High 24095280
2015 Oncogenic BRAF V600E upregulates the ketogenic enzyme HMGCL via the transcription factor Oct-1, leading to increased intracellular acetoacetate levels; acetoacetate selectively enhances binding of BRAF V600E (but not wild-type BRAF) to MEK1, promoting MEK-ERK signaling and tumor growth — a mutation-specific metabolic rewiring mechanism. Co-immunoprecipitation (BRAF V600E–MEK1 binding with/without acetoacetate), shRNA knockdown of HMGCL, metabolite measurement, Oct-1 transcriptional analysis, xenograft tumor growth assay Molecular Cell High 26145173
2018 PLX8394, a next-generation RAF inhibitor, 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 are responsible for this differential vulnerability; PLX8394 inhibits ERK signaling in tumors driven by dimeric BRAF mutants (fusions, splice variants) as well as V600 monomers. Cell-based signaling assays, RAF dimer disruption assays, structure-activity analysis of RAF isoform sequences, mutagenesis, cancer cell line panels with diverse BRAF alterations Nature Medicine High 30559419
2020 Ponatinib binds the BRAF dimer and stabilizes a distinct αC-helix conformation through interaction with a previously unrevealed allosteric site; based on this structural insight, PHI1 was developed as a BRAF dimer-selective inhibitor that shows enhanced inhibition of the second protomer when the first is occupied (positive cooperativity within the dimer). Structural binding studies, αC-helix conformation analysis, development of PHI1 inhibitor, cellular selectivity assays for BRAF monomers vs. dimers Nature Communications High 32873792
2019 BRAF inhibitors binding the V600E-mutated BRAF catalytic pocket stabilize an intermediate, inactive kinase conformation that unexpectedly enhances binary RAS:BRAF interactions independently of RAF dimerization in melanoma cells; this allosteric intramolecular communication between the kinase and RAS-binding domains may further promote paradoxical kinase activation. Luciferase-based BRAF conformation biosensors, RAS:RAF binary interaction assays, structurally diverse inhibitor panel, melanoma cell lines Science Advances Medium 31453322
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/cortactin foci, membrane protrusion) and matrix metalloprotease secretion, respectively; BRAF V600E inhibition blocks these invasion activities in vitro and reduces cortactin foci in a murine melanoma model and patient biopsies. F-actin/cortactin foci assays, ECM degradation assay, BRAF inhibitor treatment, phospho-protein analysis, genome-wide expression profiling, murine BRAF V600E model, patient biopsy analysis Cell Reports Medium 27210749
2017 Expression of the kinase-inactive Braf D631A (human D594A) isoform in mice triggers lung adenocarcinoma in vivo, acting as an initiating oncogenic event; co-expression with Kras G12V markedly enhances tumor initiation via Craf kinase activity; wild-type Braf kinase sustains Kras/Braf D631A-driven tumors, and its ablation induces excessive MAPK signaling causing oncogenic toxicity that can be rescued by Mek inhibition. Conditional knock-in mouse model (Cre-mediated), genetic epistasis (wild-type Braf allele deletion, Craf activity requirement), MEK inhibitor rescue experiments, MAPK pathway signaling analysis Nature High 28783725
2017 BRAF gene internal deletions involving the Ras-binding domain (exons 2–8) represent a mechanism of acquired resistance to dabrafenib/trametinib in melanoma; these deletions are analogous to BRAF fusions and splice variants that reactivate RAS-RAF-MEK-ERK signaling by removing the RAS-binding domain. Pre- and post-treatment tumor biopsy sequencing (foundation medicine panel), large melanoma cohort analysis (next-generation sequencing) Pigment Cell & Melanoma Research Medium 29171936
2017 A somatic BRAF splicing mutation (9 bp duplication encoding insertion of 3 amino acids in the N-terminal kinase domain lobe, p.Arg506_Lys507insLeuLeuArg) found in LCH cases enhances MAPK pathway activation in HEK293 cells and is not inhibited by vemurafenib but is inhibited by the dimer-targeting inhibitor PLX8394, indicating this mutant signals as a dimer. Whole exome sequencing, transient expression in HEK293 cells, MAPK pathway activation assays, BRAF inhibitor treatment (vemurafenib vs PLX8394) Molecular Cancer Medium 28679432
2012 Anti-BRAF autoantibodies targeting the BRAF catalytic domain were identified in rheumatoid arthritis patients; these autoantibodies stimulate BRAF activity, in contrast to anti-PAD4 autoantibodies which are inhibitory. Protein array screening of 8000 human proteins with RA patient sera, validation of BRAF as autoantigen, functional assay of antibody effect on BRAF kinase activity Autoimmunity Reviews Low 22349616
2019 BRAF oncogene drives loss of RIPK3 expression in cancer cells, suppressing necroptosis sensitivity; inhibition of BRAF can rescue RIPK3 expression and restore necroptosis sensitivity. Genome-wide bioinformatics analysis of 941 cancer cell line necroptosis sensitivity screen correlated with gene expression and mutation data; pharmacological BRAF inhibition with RIPK3 re-expression readout PLoS Biology Low 30157175
2013 BRAF V600E mutations drive constitutive MAPK pathway activation in ameloblastoma cells in vitro; the BRAF inhibitor vemurafenib potently inhibits proliferation and MAPK activation in an ameloblastoma-derived cell line. Allele-specific PCR, Sanger sequencing, VE1 immunohistochemistry, cell proliferation assay with vemurafenib, phospho-MAPK western blot in cell line Clinical Cancer Research Medium 24993163
2015 BRAF V600E inhibition attenuates TERT expression and TERT promoter activity in BRAF V600E/TERT promoter double-mutant glioma cells but not in BRAF V600E-only cells; this occurs through downregulation of ETS1 phosphorylation and expression, with ChIP confirming a functional role for ETS1 at the TERT promoter. BRAF inhibitor treatment, qRT-PCR, Western blot (ETS1 expression/phosphorylation), ChIP, luciferase TERT promoter reporter assay, ETS1 knockdown experiments Acta Neuropathologica Communications Medium 31391125
2023 SRC kinases are systematically activated in BRAF V600E colorectal cancer following BRAF ± EGFR targeted inhibition; SRC drives resistance independently of ERK signaling by inducing transcriptional reprogramming through β-catenin; this SRC activation is mediated by an autocrine prostaglandin E2 (COX2) loop, and COX2 inhibition combined with BRAF + EGFR targeting promotes durable tumor suppression in PDX models. High-throughput kinase activity mapping, cell-based signaling assays, β-catenin transcriptional reporter, COX2/prostaglandin E2 pathway analysis, patient-derived xenograft models Nature Cancer Medium 36759733
2019 In BRAF V600E-driven tumors, adaptive resistance to dual BRAF/MEK inhibition occurs through transcriptional upregulation of FGF1, which autocrinally activates FGFR to reactivate ERK; FGFR inhibition overcomes this resistance in cell lines and patient-derived xenograft models. Resistant cell line generation, pharmacologic synthetic lethal screen, FGF1 transcriptional analysis, FGFR inhibitor rescue in cells and PDX models, serum FGF1 clinical correlation Clinical Cancer Research Medium 31515463
2020 Dabrafenib (BRAF kinase inhibitor) and other BRAF/MEK/ERK pathway inhibitors protect against cisplatin- and noise-induced hearing loss in mice; oral dabrafenib represses ERK phosphorylation in cochlear cells, identifying BRAF-ERK signaling as a mediator of ototoxicity. Small-molecule kinase inhibitor screen in inner ear cell line, cochlear explant hair cell death assay, oral dabrafenib treatment in adult mice, ERK phosphorylation analysis in cochlear cells, audiological hearing loss assessment Science Advances Medium 33268358
2017 BRAF exists as a pool of at least three protein isoforms (BRAF-ref, BRAF-X1, BRAF-X2) differing in their C-terminal coding sequences; BRAF-X1 and BRAF-ref are both translated and together account for BRAF functional activities, while endogenous BRAF-X2 protein is selectively targeted for degradation by the ubiquitin-proteasome pathway. RNA-seq analysis of >4800 cancer patients, isoform-specific protein detection, proteasome inhibition experiments, functional activity assays of isoforms Molecular Cancer Medium 28454577

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Mutations of the BRAF gene in human cancer. Nature 8391 12068308
2012 Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. The New England journal of medicine 2221 23020132
2014 Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. The New England journal of medicine 1662 25265494
2014 Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. The New England journal of medicine 1522 25265492
2005 BRAF mutation predicts sensitivity to MEK inhibition. Nature 1092 16273091
2005 BRAF mutation in thyroid cancer. Endocrine-related cancer 1052 15947100
2003 BRAF mutation in papillary thyroid carcinoma. Journal of the National Cancer Institute 673 12697856
2012 The role of BRAF V600 mutation in melanoma. Journal of translational medicine 609 22554099
2018 Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer. Cancer discovery 487 29431699
2015 Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 426 26392102
2019 Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma. Nature medicine 267 31171879
2020 Clinical Development of BRAF plus MEK Inhibitor Combinations. Trends in cancer 265 32540454
2014 Activating FGFR2-RAS-BRAF mutations in ameloblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research 219 24993163
2007 BRAF(E600) in benign and malignant human tumours. Oncogene 215 17724477
2016 Resistant mechanisms to BRAF inhibitors in melanoma. Annals of translational medicine 182 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 161 30559419
2009 BRAF signaling and targeted therapies in melanoma. Hematology/oncology clinics of North America 150 19464601
2015 Metabolic Rewiring by Oncogenic BRAF V600E Links Ketogenesis Pathway to BRAF-MEK1 Signaling. Molecular cell 136 26145173
2010 BRAF as therapeutic target in melanoma. Biochemical pharmacology 134 20350535
2020 BRAF Inhibitors: Molecular Targeting and Immunomodulatory Actions. Cancers 132 32645969
2013 Clinicopathological relevance of BRAF mutations in human cancer. Pathology 127 23594689
2015 BRAF Mutation in Colorectal Cancer: An Update. Biomarkers in cancer 116 26396549
2013 Phosphorylation of BRAF by AMPK impairs BRAF-KSR1 association and cell proliferation. Molecular cell 116 24095280
2018 BRAF and MEK Inhibitors: Use and Resistance in BRAF-Mutated Cancers. Drugs 113 29488071
2018 Impact of BRAF Mutation Class on Disease Characteristics and Clinical Outcomes in BRAF-mutant Lung Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 105 30224342
2015 BRAF Mutations in Canine Cancers. PloS one 105 26053201
2014 Overcoming resistance to BRAF inhibition in BRAF-mutated metastatic melanoma. Oncotarget 104 25344914
2017 Overcoming resistance to BRAF inhibitors. Annals of translational medicine 97 29114545
2011 Role of BRAF in thyroid oncogenesis. Clinical cancer research : an official journal of the American Association for Cancer Research 97 21900390
2013 To BRAF or not to BRAF: is that even a question anymore? Journal of neuropathology and experimental neurology 95 23242278
2015 Clinical detection and categorization of uncommon and concomitant mutations involving BRAF. BMC cancer 94 26498038
2013 BRAF inhibitors in cancer therapy. Pharmacology & therapeutics 89 24325952
2017 A Braf kinase-inactive mutant induces lung adenocarcinoma. Nature 87 28783725
2023 Precision oncology for BRAF-mutant cancers with BRAF and MEK inhibitors: from melanoma to tissue-agnostic therapy. ESMO open 84 36842301
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 83 23617957
2005 Alterations of the BRAF gene in thyroid tumors. Endocrine pathology 83 16299399
2018 Current Insights of BRAF Inhibitors in Cancer. Journal of medicinal chemistry 82 29461827
2021 BRAF Gene and Melanoma: Back to the Future. International journal of molecular sciences 81 33801689
2006 Targeting BRAF in thyroid cancer. British journal of cancer 80 17179987
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 74 30157175
2014 Effects of BRAF mutations and BRAF inhibition on immune responses to melanoma. Molecular cancer therapeutics 74 25385327
2022 BRAF mutations in thyroid cancer. Current opinion in oncology 69 34636352
2014 BRAF gene: From human cancers to developmental syndromes. Saudi journal of biological sciences 68 26150740
2020 Inhibitors of BRAF dimers using an allosteric site. Nature communications 65 32873792
2016 BRAF-V600E expression correlates with ameloblastoma aggressiveness. Histopathology 65 27681305
2008 Therapeutic strategies for inhibiting oncogenic BRAF signaling. Current opinion in pharmacology 65 18644254
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 64 29674508
2019 Atypical BRAF and NRAS Mutations in Mucosal Melanoma. Cancers 62 31398831
2015 ENDOCRINE TUMORS: BRAF V600E mutations in papillary craniopharyngioma. European journal of endocrinology 61 26563980
2016 RAS and BRAF in metastatic colorectal cancer management. Journal of gastrointestinal oncology 59 27747083
2014 Alternative BRAF mutations in BRAF V600E-negative hairy cell leukaemias. British journal of haematology 58 24433452
2013 CRM1 and BRAF inhibition synergize and induce tumor regression in BRAF-mutant melanoma. Molecular cancer therapeutics 57 23615632
2018 BRAF alterations in primary brain tumors. Discovery medicine 55 30265855
2020 A BRAF new world. Critical reviews in oncology/hematology 52 32485528
2015 BRAF and MEK inhibition in melanoma. Expert opinion on drug safety 52 25648338
2021 BRAF, MEK and EGFR inhibition as treatment strategies in BRAF V600E metastatic colorectal cancer. Therapeutic advances in medical oncology 51 33747149
2020 BRAF inhibition protects against hearing loss in mice. Science advances 49 33268358
2016 Oncogenic BRAF-Mediated Melanoma Cell Invasion. Cell reports 46 27210749
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 45 31515463
2017 Beyond the BRAFV600E hotspot: biology and clinical implications of rare BRAF gene mutations in melanoma patients. The British journal of dermatology 44 28278349
2011 BRAF as a target for cancer therapy. Anti-cancer agents in medicinal chemistry 43 21426297
2023 A reversible SRC-relayed COX2 inflammatory program drives resistance to BRAF and EGFR inhibition in BRAFV600E colorectal tumors. Nature cancer 42 36759733
2021 Targeting BRAF and RAS in Colorectal Cancer. Cancers 42 34063682
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
2013 Molecular pathways: response and resistance to BRAF and MEK inhibitors in BRAF(V600E) tumors. Clinical cancer research : an official journal of the American Association for Cancer Research 41 24352648
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
2016 Antitumor Activity of BRAF Inhibitor and IFNα Combination in BRAF-Mutant Melanoma. Journal of the National Cancer Institute 36 26851802
2014 Targeting BRAF in pediatric brain tumors. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting 35 24857135
2020 BRAF: A Two-Faced Janus. Cells 34 33260892
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
2016 Combined BRAFV600E and MEK blockade for BRAFV600E-mutant gliomas. Journal of neuro-oncology 32 27848137
2015 The role of BRAF in the pathogenesis of thyroid carcinoma. Frontiers in bioscience (Landmark edition) 32 25961545
2012 BRAF mutation testing in clinical practice. Expert review of molecular diagnostics 32 22369373
2007 Mouse models for BRAF-induced cancers. Biochemical Society transactions 32 17956344
2019 TERT expression is susceptible to BRAF and ETS-factor inhibition in BRAFV600E/TERT promoter double-mutated glioma. Acta neuropathologica communications 31 31391125
2017 BRAF internal deletions and resistance to BRAF/MEK inhibitor therapy. Pigment cell & melanoma research 31 29171936
2015 Comparative Aspects of BRAF Mutations in Canine Cancers. Veterinary sciences 31 29061943
2011 Biological challenges of BRAF inhibitor therapy. Molecular oncology 31 21393075
2016 BRAF-Directed Therapy in Metastatic Colorectal Cancer. Cancer journal (Sudbury, Mass.) 30 27341594
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
2015 BRAF mutations in pediatric metanephric tumors. Human pathology 29 26014474
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
2011 BRAF inhibitors and melanoma. Cancer journal (Sudbury, Mass.) 28 22157295
2021 Epigenetic modification and BRAF gene mutation in thyroid carcinoma. Cancer cell international 27 34923978
2018 BRAF Mutations in Low-Grade Serous Ovarian Cancer and Response to BRAF Inhibition. JCO precision oncology 27 35135122
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
2014 BRAF--a new player in hematological neoplasms. Blood cells, molecules & diseases 27 24495477
2021 IGF1R/IR Mediates Resistance to BRAF and MEK Inhibitors in BRAF-Mutant Melanoma. Cancers 26 34831014

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