Loading
BRAF is a signalling kinase mutated in half of melanomas; blocking it with two drugs at once became a template for targeted therapy. This dossier gathers the 13 products (12 approved), 68 trials, 6 pathways and 1 resistance route in the corpus that involve it, with external identifiers so it can be joined to UniProt, ChEMBL, Open Targets and the rest of biology.
Serine/threonine kinase in the MAPK cascade; class I (V600) mutants are monomer-active and inhibitor-sensitive, class II/III are not.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Thyroid cancer | 40-60% | Papillary V600E | Near-universal in some PTC variants | cBioPortal (TCGA) |
| Melanoma | 45-50% | V600 mutation | cBioPortal (TCGA) | |
| Colorectal cancer | 6-18% | V600E mutation | cBioPortal: 575 of 7,237, 7.9%, in crc_msk_2026 (575 of 859 BRAF mutation records); 85 of 1,134, 7.5%, in crc_msk_2017; 88 of 1,516, 5.8%, in crc_eo_2020; 48 of 534, 9.0%, in coadread_tcga_pan_can_atlas_2018; 20 of 224, 8.9%, in coadread_tcga_pub; 111 of 619, 17.9%, in coadread_dfci_2016 (a prospective population cohort, so it captures the older, right-sided, sporadic MSI cases that trial cohorts lose); 23 of 1,015, 2.3%, in crc_sysucc_2022. BRAF mutation was found in 250 of 3,063, 8.2%, of first-line metastatic patients pooled from CAIRO, CAIRO2, COIN and FOCUS (Venderbosch 2014). | cBioPortal (TCGA) |
| Colorectal cancer | 8-12% | V600E mutation | cBioPortal (TCGA) | |
| Non-small-cell lung cancer | 3-4% | Class II and class III mutations (G469X, G466X, K601E, D594X) | cBioPortal, mutation records in luad_mskcc_2023_met_organotropism: G469A 15, G466V 8, D594G 5, G469V 4, K601E 4, D594N 3, against 31 V600E, in the 132 of 2,653 samples with any BRAF mutation (5.0%); in nsclc_ctdx_msk_2022, 60 non-V600 records against 19 V600E in the 79 of 2,621 mutated samples (3.0%); in luad_tcga_pan_can_atlas_2018, 35 non-V600 records against 9 V600E. | cBioPortal (TCGA) |
| Non-small-cell lung cancer | 2-4% | V600E and non-V600 | cBioPortal (TCGA) | |
| Colorectal cancer | 2-4% | Class II and class III mutations (D594, G466, G469, K601, N581) and fusions | 208 of 9,643 sequenced metastatic colorectal cancers, 2.2%, and 22% of all BRAF mutations found (Jones 2017). cBioPortal, mutation records in crc_msk_2026: D594G 46, G469A 9, D594N 9, G466E 6, G469R 6, G469V 5, K601E 4, N581S 4, G466V 3, against 575 V600E; BRAF fusions appear as structural variants in 24 of 7,237 samples (TRIM24-BRAF 9, MKRN1-BRAF 4). | doi.org |
| Gallbladder cancer | 3% | Mutation | Mutation in 7 of 244 samples, 2.9%, in cBioPortal gbc_mskcc_2022 and 5 of 103, 4.9%, in gbc_msk_2018; none of 32 exomes in gbc_shanghai_2014. | cBioPortal (TCGA) |
| Pancreatic ductal adenocarcinoma | 1-3% | Mutation (V600E, in-frame deletion) or fusion | cBioPortal: mutation in 22 of 2,336, 0.9% (N486_P490del 6, V600E 3, V600R 2, T599dup 2), plus 7 fusions (SND1-BRAF 3) in pdac_msk_2024; 3 of 109, all V600E, in paad_utsw_2015, where BRAF mutations were mutually exclusive with KRAS and conferred vemurafenib sensitivity in models (Witkiewicz 2015); 2 of 179 in paad_tcga_pan_can_atlas_2018 and 4 of 395 (V600E 2) in pancreas_msk_2024. 13.0% of 266 KRAS wild-type tumours carried a BRAF mutation and 6.6% a BRAF fusion (Philip 2022). Two of 71 advanced patients carried oncogenic in-frame BRAF deletions, the first clinical evidence that they respond to MAPK pathway inhibition (Aguirre 2018). | cBioPortal (TCGA) |
| Non-small-cell lung cancer | 1-2% | V600E mutation | cBioPortal, V600E records: 31 of 2,653 samples, 1.2%, in luad_mskcc_2023_met_organotropism; 18 of 915, 2.0%, in lung_msk_2017; 19 of 2,621, 0.7%, in nsclc_ctdx_msk_2022; 9 of 566, 1.6%, in luad_tcga_pan_can_atlas_2018; 5 of 230, 2.2%, in luad_tcga_pub. Any BRAF mutation is far commoner: 132 of 2,653 (5.0%), 50 of 915 (5.5%) and 41 of 566 (7.2%). BRAF of any kind was the driver in 16 of 733 fully genotyped adenocarcinomas, 2% (Kris 2014). | cBioPortal (TCGA) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
| Residue | Kind | How common | What it does | Addressed by | Defeats | Source |
|---|---|---|---|---|---|---|
| V600E 600 | Activating | About half of cutaneous melanomas; 8 to 12% of colorectal cancers; nearly all hairy cell leukaemias | Class I: signals as a RAS-independent monomer, so type I.5 RAF inhibitors work. Colorectal disease needs EGFR co-blockade. | - | Davies et al., Nature 2002 | |
| V600K 600 | Activating | About 10 to 20% of BRAF V600 melanoma | Second class I allele; same drugs, somewhat lower response rates in some series. | - | COSMIC: BRAF | |
| Class II (K601E, G469A/V, L597, fusions) 469 | Activating | not sourced | RAS-independent dimers; first-generation RAF inhibitors are ineffective or paradoxically activating. Type II (pan-RAF) inhibitors and MEK inhibitors are the route; tovorafenib is approved for BRAF-fusion paediatric low-grade glioma. | Yao et al., Nature 2017 (RAF classes) | ||
| Class III (D594, G466, N581) 594 | Other | not sourced | Kinase-impaired alleles that amplify upstream RAS signalling through CRAF; treated by targeting the upstream receptor, not BRAF. | none in corpus | - | Yao et al., Nature 2017 (RAF classes) |
Frequencies are quoted from the source on each row; a blank means no figure was sourced, not that it is rare. Domain boundaries are approximate. Sources for the map: Cancer Hotspots (MSK) · COSMIC: BRAF.
| Modality | Approved | Phase 2 |
|---|---|---|
| Small molecule 9 | - | |
| Test or device 3 | - | |
| Cell therapy 1 | - |
| Trial | Setting | Result | Products | ||
|---|---|---|---|---|---|
| 3 | Active | A Randomized, Double-blind, Placebo-controlled Phase III Study to Evaluate the Efficacy and Safety of Dabrafenib Plus Trametinib in Previously Treated Patients With Locally Advanced or Metastatic, Radio-active Iodine Refractory BRAFV600E Mutation-positive Differentiated Thyroid Cancer (DTC) | - | ||
BREAKWATER NCT04607421 | 3 | Positive | First-line BRAF V600E-mutant metastatic colorectal cancer: encorafenib + cetuximab + mFOLFOX6 (or FOLFIRI) vs chemotherapy ± bevacizumab | OS 30.3 vs 15.1 months (HR 0.49); PFS 12.8 vs 7.1 months. | |
| 3 | Active | A Randomized, Controlled Phase 3 Study of Cabozantinib (XL184) in Combination With Atezolizumab Versus Sorafenib in Subjects With Advanced Hepatocellular Carcinoma Who Have Not Received Previous Systemic Anticancer Therapy | - | ||
CAIRO5 NCT02162563 | 3 | Mixed | Initially unresectable colorectal liver metastases, stratified by sidedness and RAS/BRAF status: a doublet plus bevacizumab, FOLFOXIRI plus bevacizumab, or a doublet plus panitumumab, with central resectability review every two months | FOLFOXIRI plus bevacizumab better than a doublet for right-sided or RAS/BRAF-mutant disease; panitumumab no better than bevacizumab for left-sided wild-type disease. | |
DREAMseq (ECOG-ACRIN EA6134) NCT02224781 | 3 | Positive | Untreated BRAF V600 metastatic melanoma: nivolumab + ipilimumab then dabrafenib + trametinib at progression, vs the reverse sequence | 2-year OS 71.8% vs 51.5%. | |
AAML1031 NCT01371981 | 3 | Mixed | Newly diagnosed acute myeloid leukaemia in patients under 30: standard chemotherapy with or without bortezomib (randomised), and for high allelic ratio FLT3-ITD disease the addition of sorafenib to chemotherapy and as maintenance (non-randomised cohorts) | Bortezomib added to chemotherapy did not improve three-year event-free survival (44.8 percent against 47.0 percent) and added toxicity; sorafenib for high allelic ratio FLT3-ITD disease roughly halved the hazard of an event compared with matched patients treated without it. | |
IMspire150 NCT02908672 | 3 | Positive | Untreated BRAF V600-mutant advanced melanoma: atezolizumab or placebo added to vemurafenib and cobimetinib after a 28-day run-in of the two targeted drugs | Atezolizumab added to vemurafenib and cobimetinib prolonged investigator-assessed progression-free survival in BRAF V600-mutant melanoma, without an overall survival benefit; approved in July 2020. | |
BEACON CRC NCT02928224 | 3 | Positive | BRAF V600E-mutant metastatic colorectal cancer after one or two prior lines: encorafenib plus cetuximab with or without binimetinib, versus irinotecan-based chemotherapy plus cetuximab | Median overall survival 9.3 months (encorafenib-cetuximab, with or without binimetinib) vs 5.9 months (chemotherapy plus cetuximab); response rate 20% (doublet) vs 2%. | |
IMblaze370 NCT02788279 | 3 | Negative | Previously treated metastatic colorectal adenocarcinoma, mostly microsatellite-stable: atezolizumab with cobimetinib, or atezolizumab alone, against regorafenib | Median overall survival 8.87 months with atezolizumab and cobimetinib against 8.51 months with regorafenib (hazard ratio 1.00). | |
COLUMBUS NCT01909453 | 3 | Positive | Advanced BRAF V600 melanoma: encorafenib + binimetinib vs vemurafenib vs encorafenib | PFS 14.9 vs 7.3 months (HR 0.54); median OS 33.6 months. | |
REFLECT NCT01761266 | 3 | Positive | First-line unresectable HCC: lenvatinib vs sorafenib (non-inferiority) | OS 13.6 vs 12.3 months, non-inferior (HR 0.92). | |
COMBI-AD NCT01682083 | 3 | Positive | Resected stage III BRAF V600-mutant melanoma: adjuvant dabrafenib + trametinib 1 year vs placebo | 10-year RFS 48% vs 32%; DMFS 63% vs 48%. | |
SARAH and SIRveNIB NCT01482442 | 3 | Negative | Locally advanced HCC: yttrium-90 radioembolisation vs sorafenib | OS not improved; fewer adverse events. | |
coBRIM NCT01689519 | 3 | Positive | Untreated unresectable or metastatic BRAF V600-mutant melanoma: vemurafenib plus cobimetinib versus vemurafenib plus placebo | Median progression-free survival 12.3 vs 7.2 months (HR 0.58); median overall survival 22.3 vs 17.4 months (HR 0.70). | |
COMBI-d NCT01584648 | 3 | Positive | Untreated unresectable or metastatic BRAF V600E or V600K melanoma: dabrafenib plus trametinib versus dabrafenib plus placebo | Median progression-free survival 11.0 vs 8.8 months; median overall survival 25.1 vs 18.7 months (HR 0.71); pooled COMBI-d/v 5-year overall survival 34%. | |
CORRECT NCT01103323 | 3 | Positive | Metastatic colorectal cancer progressing after all approved standard therapies: regorafenib 160 mg daily, three weeks on and one off, with best supportive care, against placebo | Median overall survival 6.4 against 5.0 months (hazard ratio 0.77); grade 3 or worse hand-foot skin reaction in 17 percent. | |
DECISION NCT00984282 | 3 | Positive | Radioiodine-refractory differentiated thyroid cancer: sorafenib vs placebo | PFS 10.8 vs 5.8 months; HR 0.59. | - |
LCH-III NCT00276757 | 3 | Positive | Multisystem Langerhans cell histiocytosis in children: risk-organ-positive patients randomised to vinblastine-prednisone with or without methotrexate (12 months total); risk-organ-negative responders randomised to 6 vs 12 months of vinblastine-prednisone | 12 vs 6 months of vinblastine-prednisone: 5-year reactivation 37% vs 54% in risk-organ-negative disease; methotrexate added no benefit. | |
PRIME NCT00364013 | 3 | Positive | Previously untreated metastatic colorectal cancer: FOLFOX4 with or without panitumumab, analysed by extended RAS status | In RAS wild-type disease, overall survival 26.0 against 20.2 months (hazard ratio 0.78); patients with non-exon-2 RAS mutations did worse with panitumumab. | |
SHARP NCT00105443 | 3 | Positive | Advanced HCC, Child-Pugh A, no prior systemic therapy: sorafenib vs placebo | OS 10.7 vs 7.9 months, HR 0.69. | |
| 3 | Active | A PHASE 3, RANDOMIZED, DOUBLE-BLIND STUDY OF ENCORAFENIB AND BINIMETINIB PLUS PEMBROLIZUMAB VERSUS PLACEBO PLUS PEMBROLIZUMAB IN PARTICIPANTS WITH BRAF V600E/K MUTATION-POSITIVE METASTATIC OR UNRESECTABLE LOCALLY ADVANCED MELANOMA | - | ||
| 3 | Active | Adjuvant Encorafenib & Binimetinib vs. Placebo in Fully Resected Stage IIB/C BRAF V600E/K Mutated Melanoma: a Randomized Triple-blind Phase III Study in Collaboration With the EORTC Melanoma Group | - | ||
| 3 | Active | LOGGIC/FIREFLY-2: A Phase 3, Randomized, International Multicenter Trial of DAY101 Monotherapy Versus Standard of Care Chemotherapy in Patients With Pediatric Low-Grade Glioma Harboring an Activating RAF Alteration Requiring First-Line Systemic Therapy | - | ||
| 3 | Active | Early Identification and Treatment of Occult Metastatic Disease in Stage III Colon Cancer | - | ||
SAFIR-ABC10 NCT05615818 | 3 | Recruiting | Advanced biliary cancer (intrahepatic, perihilar or distal cholangiocarcinoma, or gallbladder carcinoma) after induction gemcitabine and cisplatin: molecular targeted maintenance therapy matched to the tumour's alteration versus standard of care, international platform phase 3 | - | |
ORIENT-32 NCT03794440 | 2/3 | Positive | First-line unresectable hepatocellular carcinoma, China (mostly hepatitis B-related): sintilimab plus the bevacizumab biosimilar IBI305 vs sorafenib | OS HR 0.57; PFS HR 0.56. | |
ZGDH3 (donafenib vs sorafenib) NCT02645981 | 2/3 | Positive | First-line unresectable or metastatic hepatocellular carcinoma, China: donafenib vs sorafenib | OS 12.1 vs 10.3 months, HR 0.83. | |
| 2/3 | Recruiting | DETERMINE (Determining Extended Therapeutic Indications for Existing Drugs in Rare Molecularly Defined Indications Using a National Evaluation Platform Trial): An Umbrella-Basket Platform Trial to Evaluate the Efficacy of Targeted Therapies in Rare Adult, Paediatric and Teenage/Young Adult (TYA) Cancers With Actionable Genomic Alterations, Including Common Cancers With Rare Actionable Alterations. | - | ||
| 2/3 | Recruiting | DETERMINE (Determining Extended Therapeutic Indications for Existing Drugs in Rare Molecularly Defined Indications Using a National Evaluation Platform Trial): An Umbrella-Basket Platform Trial to Evaluate the Efficacy of Targeted Therapies in Rare Adult, Paediatric and Teenage/Young Adult (TYA) Cancers With Actionable Genomic Alterations, Including Common Cancers With Rare Actionable Alterations. | - | ||
| 2/3 | Active | Randomized Trial of Consolidation Targeted Adjuvant Therapy With Encorafenib and Cetuximab Versus Usual Care for Patients With Stage II/III BRAF V600E Colon Cancer | - |
Alternative MAPK activation.
This KEGG map traces the step-by-step genetic route from normal bowel lining to colorectal cancer: APC loss unleashes Wnt, KRAS mutation drives growth, then TP53 and TGF-beta/SMAD4 loss remove the last brakes, or alternatively mismatch repair fails and mutations pile up. Knowing which route a tumour took decides which drugs work.
Which nodes have drugs →This KEGG map shows the two genetic roads to glioblastoma: primary tumours amplify EGFR and lose PTEN and p16, secondary tumours from lower-grade astrocytomas over-express PDGF and CDK4 and lose TP53 and RB. It explains why growth-factor and cell-cycle drugs are the main targeted options in brain tumours, and why paediatric low-grade gliomas with BRAF changes respond to MAPK inhibitors.
Which nodes have drugs →KEGG's melanoma map shows BRAF or NRAS mutations driving the MAPK growth relay, PTEN loss driving PI3K/AKT, and loss of the CDKN2A brakes (p16 and p14ARF) on CDK4/6 and p53. BRAF plus MEK inhibitors and immune checkpoint antibodies have transformed treatment.
Which nodes have drugs →This KEGG map shows the order of genetic hits that turn normal pancreatic duct cells into ductal adenocarcinoma: KRAS mutation first, then loss of the p16 brake, then loss of TP53, SMAD4 and BRCA2. It matters because nearly every pancreatic cancer is driven by KRAS, which until recently had no drug.
Which nodes have drugs →The RAS-MAPK pathway is the cell's 'divide' relay. A signal at the surface flips RAS on, which passes to RAF, MEK, and ERK, which tell the nucleus to make the cell divide. KRAS and BRAF mutations jam it in the on position.
Which nodes have drugs →This KEGG map shows thyroid cancers driven by one relay, the MAPK pathway: RET or NTRK fusions and BRAF mutations in papillary tumours, RAS mutations or PAX8-PPARG fusion in follicular tumours, and TP53 loss marking anaplastic cancer. It matters because RET, NTRK and BRAF alterations each have their own drug, and MAPK blockade can restore iodine uptake.
Which nodes have drugs →| Assay | Platform | Cut-off | Gates |
|---|---|---|---|
| cobas 4800 BRAF V600 Mutation Test Roche Molecular Systems · FDA CDx 2011 | PCR | V600 mutation detected | |
| THxID BRAF Kit bioMérieux · FDA CDx 2013 | PCR | V600E or V600K detected | |
| therascreen BRAF V600E RGQ PCR Kit QIAGEN · FDA CDx 2020 | PCR | V600E detected (colorectal cancer, encorafenib plus cetuximab) | |
| FoundationOne CDx Foundation Medicine (Roche) · FDA CDx 2017 | NGS tissue | Per companion claim: EGFR, ALK, BRAF V600, ERBB2 amplification, KRAS wild-type, BRCA1/2 and HRR genes, PIK3CA, MET exon 14, RET, FGFR2 fusions, IDH1, NTRK fusions; MSI-high; TMB at least 10 mutations per megabase | |
| Oncomine Dx Target Test Thermo Fisher Scientific · FDA CDx 2017 | NGS tissue | Per companion claim: BRAF V600E (dabrafenib plus trametinib), ROS1 fusions (crizotinib), EGFR (gefitinib), RET fusions (pralsetinib), MET exon 14 (tepotinib), EGFR exon 20 insertions |
| Cell line | Identifiers | Why it is used |
|---|---|---|
| A-375 | CVCL_0132 · ACH-000219 | Melanoma, V600E. |
| SK-MEL-28 | CVCL_0526 · ACH-000615 | Melanoma, V600E. |
| HT-29 | CVCL_0320 · ACH-000552 | Colorectal, V600E; the model for EGFR co-blockade. |
| RKO | CVCL_0504 · ACH-000943 | Colorectal, V600E, MSI-high. |
| COLO 205 | CVCL_0218 · ACH-001039 | Colorectal, V600E. |
| WM-266-4 | CVCL_2765 · ACH-001239 | Melanoma, V600D. |
| 8505C | CVCL_1054 · ACH-001307 | Anaplastic thyroid, V600E. |
| MDA-MB-231 | CVCL_0062 · ACH-000768 | Breast, G464V (class III). |
Why unresolved. BREAKWATER showed higher response and progression-free survival; overall survival maturity, the role of the chemotherapy backbone, and MSI-high BRAF patients (who may do better with immunotherapy) remain open.
What would answer it. Mature overall survival, MSI-stratified analyses, and a comparison with immunotherapy in MSI-high BRAF-mutant disease.
Query for this target: (TITLE:"BRAF" OR ABSTRACT:"BRAF") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about BRAF, not a curated reading list.
The dossier as machine-readable JSON, at /api/v1/dossiers/braf.json: identifiers from HGNC, Ensembl, UniProt and ChEMBL, products with status, trials, pathways, hotspots, open questions and assays. The full entity record is in the open API at /api/v1/entities/braf.json. Licence CC BY-NC 4.0.