Langerhans cell histiocytosis specific to adulthood

Summary

Langerhans cell histiocytosis specific to adulthood (MONDO:0017029) is a disease with 1 cohort gene and 52 clinical trials. Molecularly, BRAF V600 confers sensitivity to Vemurafenib in Langerhans-cell Histiocytosis (CIViC Level B); 10 further subtype–drug associations are mapped below. Top therapeutic interventions include mercaptopurine anhydrous, larotrectinib, and clofarabine.

At a glance

• Cohort genes: 1
• Clinical trials: 52
• Precision-medicine evidence (CIViC): 11 subtype–drug associations

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Langerhans cell histiocytosis specific to adulthood
Mondo ID	MONDO:0017029
Orphanet	264750
NCIT	C114929
UMLS	C3900100
MedGen	859694
GARD	0025086
Is cancer (heuristic)	no

Also known as: adult Langerhans cell histiocytosis · histiocytosis X specific to adulthood · Langerhans cell granulomatosis specific to adulthood · Langerhans cell histiocytosis

Data availability: 17 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › respiratory system disorder › lower respiratory tract disorder › lung disorder › interstitial lung disease › interstitial lung disease specific to adulthood › Langerhans cell histiocytosis specific to adulthood

Related subtypes (1): pulmonary sarcoidosis

Subtypes (1): adult pulmonary Langerhans cell histiocytosis

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BRAF	Orphanet:1340	Cardiofaciocutaneous syndrome
BRAF	Orphanet:146	Differentiated thyroid carcinoma
BRAF	Orphanet:251615	Pilomyxoid astrocytoma
BRAF	Orphanet:389	Langerhans cell histiocytosis
BRAF	Orphanet:500	Noonan syndrome with multiple lentigines
BRAF	Orphanet:54595	Craniopharyngioma
BRAF	Orphanet:58017	Classic hairy cell leukemia
BRAF	Orphanet:626	Large/giant congenital melanocytic nevus
BRAF	Orphanet:648	Noonan syndrome
BRAF	Orphanet:840	Syringocystadenoma papilliferum
BRAF	Orphanet:96253	Cushing disease

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
civic_only	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	civic_evidence

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
calcaneal tendon	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BRAF	7,394

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BRAF	P15056	131

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 39. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by MRAS-complex mutants	1	2855.0×	0.004	BRAF
Signalling to p38 via RIT and RIN	1	2284.0×	0.004	BRAF
Negative feedback regulation of MAPK pathway	1	1903.3×	0.004	BRAF
ARMS-mediated activation	1	1631.4×	0.004	BRAF
Prolonged ERK activation events	1	1427.5×	0.004	BRAF
SHOC2 M1731 mutant abolishes MRAS complex function	1	1427.5×	0.004	BRAF
Gain-of-function MRAS complexes activate RAF signaling	1	1427.5×	0.004	BRAF
Signaling by FGFR3	1	1142.0×	0.004	BRAF
Signaling by FGFR4	1	1038.2×	0.004	BRAF
Frs2-mediated activation	1	951.7×	0.004	BRAF
Signaling by FGFR1	1	815.7×	0.004	BRAF
Spry regulation of FGF signaling	1	713.8×	0.005	BRAF
Signalling to ERKs	1	601.0×	0.005	BRAF
Negative regulation of FGFR3 signaling	1	439.2×	0.005	BRAF
Signaling by RAS mutants	1	423.0×	0.005	BRAF
Negative regulation of FGFR4 signaling	1	407.9×	0.005	BRAF
Signaling by FGFR2	1	407.9×	0.005	BRAF
Negative regulation of FGFR1 signaling	1	368.4×	0.005	BRAF
Negative regulation of FGFR2 signaling	1	368.4×	0.005	BRAF
Signaling by FGFR	1	346.1×	0.005	BRAF
RAF activation	1	335.9×	0.005	BRAF
Signaling by high-kinase activity BRAF mutants	1	317.2×	0.005	BRAF
MAP2K and MAPK activation	1	285.5×	0.005	BRAF
Signaling by RAF1 mutants	1	278.5×	0.005	BRAF
Negative regulation of MAPK pathway	1	265.6×	0.005	BRAF
Signaling by moderate kinase activity BRAF mutants	1	253.8×	0.005	BRAF
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	253.8×	0.005	BRAF
Signaling downstream of RAS mutants	1	253.8×	0.005	BRAF
Oncogenic MAPK signaling	1	248.3×	0.005	BRAF
Signaling by NTRK1 (TRKA)	1	196.9×	0.007	BRAF

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
CD4-positive or CD8-positive, alpha-beta T cell lineage commitment	1	5617.3×	0.003	BRAF
positive regulation of axon regeneration	1	3370.4×	0.003	BRAF
negative regulation of synaptic vesicle exocytosis	1	3370.4×	0.003	BRAF
CD4-positive, alpha-beta T cell differentiation	1	2808.7×	0.003	BRAF
myeloid progenitor cell differentiation	1	2407.4×	0.003	BRAF
positive regulation of D-glucose transmembrane transport	1	2106.5×	0.003	BRAF
head morphogenesis	1	2106.5×	0.003	BRAF
establishment of protein localization to membrane	1	1872.4×	0.003	BRAF
negative regulation of fibroblast migration	1	1532.0×	0.003	BRAF
endothelial cell apoptotic process	1	1296.3×	0.003	BRAF
regulation of T cell differentiation	1	1203.7×	0.003	BRAF
face development	1	802.5×	0.003	BRAF
synaptic vesicle exocytosis	1	766.0×	0.003	BRAF
positive regulation of peptidyl-serine phosphorylation	1	766.0×	0.003	BRAF
stress fiber assembly	1	766.0×	0.003	BRAF
postsynaptic modulation of chemical synaptic transmission	1	674.1×	0.004	BRAF
positive regulation of axonogenesis	1	581.1×	0.004	BRAF
thyroid gland development	1	543.6×	0.004	BRAF
negative regulation of endothelial cell apoptotic process	1	495.6×	0.004	BRAF
T cell differentiation in thymus	1	411.0×	0.005	BRAF
positive regulation of substrate adhesion-dependent cell spreading	1	374.5×	0.005	BRAF
substrate adhesion-dependent cell spreading	1	343.9×	0.005	BRAF
thymus development	1	337.0×	0.005	BRAF
ERK1 and ERK2 cascade	1	318.0×	0.005	BRAF
positive regulation of stress fiber assembly	1	312.1×	0.005	BRAF
visual learning	1	306.4×	0.005	BRAF
long-term synaptic potentiation	1	280.9×	0.005	BRAF
epidermal growth factor receptor signaling pathway	1	247.8×	0.006	BRAF
somatic stem cell population maintenance	1	247.8×	0.006	BRAF
cellular response to xenobiotic stimulus	1	240.7×	0.006	BRAF

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
BRAF	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BRAF	48	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	BRAF
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF
SORAFENIB	4	BRAF
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
DABRAFENIB	4	BRAF
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF
DASATINIB	4	BRAF
ERLOTINIB	4	BRAF
GEFITINIB	4	BRAF
IMATINIB	4	BRAF
MASITINIB	3	BRAF
AVUTOMETINIB	3	BRAF
NAPORAFENIB	3	BRAF
QUERCETIN	3	BRAF
MOTESANIB	3	BRAF
DORAMAPIMOD	2	BRAF
FORETINIB	2	BRAF
REBASTINIB	2	BRAF
CEP-32496	2	BRAF
BAFETINIB	2	BRAF

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
BRAF	1,442	Binding:1400, Functional:37, ADMET:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
BRAF	1,442

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

27 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF
SORAFENIB	4	BRAF
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
PAZOPANIB	4	BRAF
DASATINIB	4	BRAF
ERLOTINIB	4	BRAF
GEFITINIB	4	BRAF
IMATINIB	4	BRAF
MASITINIB	3	BRAF
AVUTOMETINIB	3	BRAF
NAPORAFENIB	3	BRAF
QUERCETIN	3	BRAF
MOTESANIB	3	BRAF
DORAMAPIMOD	2	BRAF
FORETINIB	2	BRAF
REBASTINIB	2	BRAF
CEP-32496	2	BRAF
BAFETINIB	2	BRAF

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	BRAF
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 52.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	34
Not specified	8
PHASE2/PHASE3	3
PHASE1	3
PHASE3	2
PHASE4	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05284942	PHASE4	UNKNOWN	Central China Rosai-Dorfman Disease Registry
NCT02205762	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	LCH-IV, International Collaborative Treatment Protocol for Children and Adolescents With Langerhans Cell Histiocytosis
NCT02670707	PHASE3	RECRUITING	Vinblastine/Prednisone Versus Single Therapy With Cytarabine for Langerhans Cell Histiocytosis (LCH)
NCT04773366	PHASE3	RECRUITING	A Prospective Study for the Treatment of Children With Newly Diagnosed LCH Using a Cytarabine Contained Protocol
NCT07440290	PHASE2/PHASE3	NOT_YET_RECRUITING	DETERMINE Trial Treatment Arm 07: Dabrafenib in Combination With Trametinib in Adult, Paediatric and Teenage/Young Adult Patients With BRAF V600 Mutation-Positive Cancers.
NCT00176826	PHASE2/PHASE3	TERMINATED	T-Cell Depletion and Stem Cell Transplant for Immune Deficiencies and Histiocytic Disorders
NCT01966367	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	CD34+ (Non-Malignant) Stem Cell Selection for Patients Receiving Allogeneic Stem Cell Transplantation
NCT02425904	PHASE2	ACTIVE_NOT_RECRUITING	Study of Clofarabine in Patients With Recurrent or Refractory Langerhans Cell Histiocytosis and LCH-related Disorders
NCT02523040	PHASE2	ACTIVE_NOT_RECRUITING	Lenalidomide for Adult Histiocyte Disorders
NCT03155620	PHASE2	ACTIVE_NOT_RECRUITING	Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
NCT03210714	PHASE2	ACTIVE_NOT_RECRUITING	Erdafitinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With FGFR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213652	PHASE2	ACTIVE_NOT_RECRUITING	Ensartinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With ALK or ROS1 Genomic Alterations (A Pediatric MATCH Treatment Trial)
NCT03213704	PHASE2	ACTIVE_NOT_RECRUITING	Larotrectinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With NTRK Fusions (A Pediatric MATCH Treatment Trial)
NCT03698994	PHASE2	ACTIVE_NOT_RECRUITING	Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial)
NCT04195555	PHASE2	ACTIVE_NOT_RECRUITING	Ivosidenib in Treating Patients With Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With IDH1 Mutations (A Pediatric MATCH Treatment Trial)
NCT04284774	PHASE2	ACTIVE_NOT_RECRUITING	Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial
NCT04320888	PHASE2	ACTIVE_NOT_RECRUITING	Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediatric MATCH Treatment Trial
NCT05828069	PHASE2	RECRUITING	A Study With Tovorafenib (DAY101) as a Treatment Option for Progressive, Relapsed, or Refractory Langerhans Cell Histiocytosis
NCT05997602	PHASE2	RECRUITING	To Evaluate the Efficacy, Safety, and PK Characteristics of FCN-159 in Pediatric Patients With Refractory/Recurrent LCH
NCT06153173	PHASE2	RECRUITING	Mirdametinib in Histiocytic Disorders
NCT06582745	PHASE2	RECRUITING	Targeted Approach to Langerhans Cell Histiocytosis (LCH) Using MEK Inhibitor, Trametinib
NCT07022834	PHASE2	RECRUITING	Real-world Study of Darafenib or Trametinib and Clofarabine for High-risk/Recurrent/Refractory Langerhans Cell Histiocytosis in Children
NCT07187193	PHASE2	RECRUITING	Efficacy and Safety of Low-Dose Cytarabine Combined With Thalidomide in Adult Patients With Untreated LCH
NCT07204041	PHASE2	ACTIVE_NOT_RECRUITING	Efficacy and Safety of XTD Regimen (Selinexor, Thalidomide and Dexamethasone) in Adult Patients With Relapsed/Refractory LCH
NCT00176865	PHASE2	COMPLETED	Stem Cell Transplant for Immunologic or Histiocytic Disorders
NCT00588536	PHASE2	COMPLETED	Study of Sequential Administration of Oral 6-Thioguanine After Methotrexate in Patients With LCH
NCT01273766	PHASE2	COMPLETED	Deferasirox in Treating Iron Overload Caused By Blood Transfusions in Patients With Hematologic Malignancies
NCT01395004	PHASE2	COMPLETED	A Study to Test the Ability of and Safety of GSK2110183 in Treating Langerhans Cell Histiocytosis
NCT01796405	PHASE2	WITHDRAWN	Clofarabine for Langerhans in Pedi
NCT02389400	PHASE2	COMPLETED	Methotrexate and Cytosine in Adult Langerhans Cell Histiocytosis
NCT03096782	PHASE2	COMPLETED	Umbilical Cord Blood Transplant With Added Sugar and Chemotherapy and Radiation Therapy in Treating Patients With Leukemia or Lymphoma
NCT03213665	PHASE2	COMPLETED	Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (A Pediatric MATCH Treatment Trial)
NCT03213678	PHASE2	COMPLETED	Samotolisib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial)
NCT03220035	PHASE2	COMPLETED	Vemurafenib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With BRAF V600 Mutations (A Pediatric MATCH Treatment Trial)
NCT03233204	PHASE2	COMPLETED	Olaparib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Defects in DNA Damage Repair Genes (A Pediatric MATCH Treatment Trial)
NCT03270020	PHASE2	COMPLETED	Denosumab for the Treatment of Adult LCH
NCT03526250	PHASE2	COMPLETED	Palbociclib in Treating Patients With Relapsed or Refractory Rb Positive Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Activating Alterations in Cell Cycle Genes (A Pediatric MATCH Treatment Trial)
NCT03585686	PHASE2	UNKNOWN	A Combination of Vemurafenib, Cytarabine and 2-chlorodeoxyadenosine in Children With LCH and BRAF V600E Mutation
NCT04120519	PHASE2	UNKNOWN	Thalidomide, Cyclophosphamide and Dexamethasone for Recurrent/Refractory Adult Langerhans Cell Histiocytosis
NCT04121819	PHASE2	UNKNOWN	AraC for Newly Diagnosed Adult Langerhans Cell Histiocytosis

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MERCAPTOPURINE ANHYDROUS	4	7
LAROTRECTINIB	4	4
CLOFARABINE	4	3
VEMURAFENIB	4	3
CLADRIBINE	4	2
ENSARTINIB	4	2
ERDAFITINIB	4	2
IVOSIDENIB	4	2
SELPERCATINIB	4	2
SELUMETINIB	4	2
TAZEMETOSTAT	4	2
VINBLASTINE	4	2
DABRAFENIB	4	1
DEFERASIROX	4	1
INDOMETHACIN	4	1
THIOGUANINE	4	1
TOVORAFENIB	4	1
TRAMETINIB	4	1
TIPIFARNIB	3	2
AFURESERTIB	3	1
LUVOMETINIB	2	3
SAMOTOLISIB	2	2
ULIXERTINIB	2	2
MIRDAMETINIB	2	1
CHEMBL3415553	0	3
CHEMBL4209555	0	3
PLX-4720	0	3
CHEMBL4788494	0	2
CHEMBL5398431	0	2
CHEMBL5430810	0	2

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 11 predictive associations from 12 curated evidence items.

Molecular subtype	Therapy	Effect	Level	CIViC
BRAF V600	Vemurafenib	Sensitivity/Response	CIViC B	EID11302 +1
ARAF Mutation	Cobimetinib	Sensitivity/Response	CIViC B	EID11297
BRAF Non-V600	Cobimetinib	Sensitivity/Response	CIViC B	EID11299
BRAF V600E	Dabrafenib	Sensitivity/Response	CIViC B	EID11303
NRAS Mutation OR KRAS Mutation OR RAF1 Mutation OR MAP2K1 Mutation OR MAP2K2 Mutation	Cobimetinib	Sensitivity/Response	CIViC B	EID11329
BRAF N486_P490	Trametinib	Sensitivity/Response	CIViC C	EID11300
MAP2K1 E102_I103delEI	Trametinib	Sensitivity/Response	CIViC C	EID6447
MAP2K1 K57_G61del	Trametinib	Sensitivity/Response	CIViC C	EID11301
MIGA1::BRAF Fusion	Tunlametinib + BRAF Inhibitor	Sensitivity/Response	CIViC D	EID8030
MAP2K1 56_61QKQKVG>R	Trametinib	Resistance	CIViC D	EID6384
MAP2K1 C121S AND MAP2K1 G128D	Trametinib	Resistance	CIViC D	EID6385