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 7 products (7 approved), 9 trials, 1 pathway 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.
Biology
Serine/threonine kinase in the MAPK cascade; class I (V600) mutants are monomer-active and inhibitor-sensitive, class II/III are not.
- Melanoma
- Colorectal
- Thyroid
- NSCLC
- Glioma (paediatric)
Elsewhere: identifiers and databases
Built from HGNC, Ensembl, UniProt and ChEMBL idsHow common it is, by cancer
Full matrix →| 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 | 8-12% | V600E mutation | cBioPortal (TCGA) | |
| Non-small-cell lung cancer | 2-4% | V600E and non-V600 | cBioPortal (TCGA) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Mutation hotspots and which drugs address them
| 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.
Products by modality and phase
Browse products →| Modality | Approved |
|---|---|
| Small molecule 7 |
Trials
Evidence ranking →| Trial | Phase | Status | Setting | Result | Products |
|---|---|---|---|---|---|
| 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. | |
| 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%. | |
| 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. | |
| DECISION NCT00984282 | 3 | Positive | Radioiodine-refractory differentiated thyroid cancer: sorafenib vs placebo | PFS 10.8 vs 5.8 months; HR 0.59. | |
| 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. | |
| ROAR (anaplastic thyroid cancer cohort) NCT02034110 | 2 | Positive | BRAF V600E-mutant anaplastic thyroid cancer: dabrafenib + trametinib | ORR 56%; median OS 15 months. |
Resistance routes that involve this target
Unaddressed routes →Alternative MAPK activation.
- Combination with MEK/ERK inhibitors; re-biopsy-guided therapy
Pathways where it is a node
Pathway-to-drug matrix →- RAS / RAF / MEK / ERK (MAPK)Node: RAF (BRAF) · 3 druggable nodes
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 →
Companion diagnostics and assays
Assay registry →| 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 |
Preclinical models
All models →| 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). |
- Braf CA (V600E) conditional (Cre-activated Braf V600E used in melanoma, lung, thyroid and colon models) Dankort et al., Nat Genet 2009
Open questions
All open questions →- 01
Does BREAKWATER's first-line encorafenib plus cetuximab plus chemotherapy improve overall survival enough to displace chemotherapy plus bevacizumab for every BRAF V600E colorectal patient?
clinicalclinicWhy 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.
Source: BREAKWATER (ClinicalTrials.gov)
Ideas and companies
Key papers and the live literature
Preprints →- BREAKWATER: encorafenib plus cetuximab with chemotherapy as first treatment for BRAF V600E-mutated colorectal cancer · New England Journal of Medicine 2025
- Cancer genome landscapes: about 140 driver genes, and each tumour needs only a handful · Science 2013
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.
Export
The dossier as machine-readable 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 4.0.