Laryngeal squamous cell carcinoma

Summary

Laryngeal squamous cell carcinoma (MONDO:0005595) is a cancer with 13 cohort genes (8 GWAS associations across 2 studies; 4 CIViC-evidence somatic drivers; 4 ClinVar predisposition records) and 132 clinical trials. Molecularly, BRAF V600E confers sensitivity to Vemurafenib in Laryngeal Squamous Cell Carcinoma (CIViC Level C). Top therapeutic interventions include cisplatin, lapatinib, and cetuximab.

At a glance

• Classification: Cancer
• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Cohort genes: 13
• GWAS associations: 8
• ClinVar variants: 4
• Clinical trials: 132
• Precision-medicine evidence (CIViC): 1 subtype–drug association

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	4.61	Europe	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	laryngeal squamous cell carcinoma
Mondo ID	MONDO:0005595
EFO	EFO:0006352
Orphanet	494550
DOID	DOID:2876
NCIT	C4044
SNOMED CT	405822008
UMLS	C0280324
MedGen	83630
GARD	0017908
Anatomy (UBERON)	UBERON:0001737
Is cancer (heuristic)	yes

Also known as: epidermoid carcinoma of larynx · epidermoid carcinoma of the larynx · laryngeal epidermoid carcinoma · laryngeal squamous cell carcinoma · laryngeal throat squamous cell cancer · larynx epidermoid carcinoma · larynx squamous cell carcinoma · LXSC · squamous cell carcinoma of larynx · squamous cell carcinoma of the larynx

Data availability: 4 ClinVar variants · 8 GWAS associations (2 studies) · 168 cell lines.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › cancer › respiratory system cancer › larynx cancer › laryngeal carcinoma › laryngeal squamous cell carcinoma

Related subtypes (7): glottis carcinoma, laryngeal mucoepidermoid carcinoma, carcinoma of supraglottis, subglottis carcinoma, larynx carcinoma in situ, laryngeal adenoid cystic carcinoma, laryngeal small cell carcinoma

Subtypes (4): larynx verrucous carcinoma, glottis squamous cell carcinoma, subglottis squamous cell carcinoma, supraglottis squamous cell carcinoma

Genetics & variants

GWAS landscape

8 GWAS associations across 2 studies. Top hits map to 6 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs174549	1e-20	FADS1, FADS2	?	1.37
rs2857595	2e-15	NCR3 - UQCRHP1	?	1.3
rs10492336	4e-14	GLULP5 - LINC02459	?	1.41
rs142021700	3e-09	RTTN	C	3.95
rs310518	7e-08	VCAN	?	1.27
rs77045180	1e-07	AKR1C1	T	2.51
rs40129	4e-07	LINC02177	?	1.21
rs9445023	7e-07	U3 - ATF1P1	?	1.32

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST002597	Wei Q	2014	993	1,995	Genome-wide association study identifies three susceptibility loci for laryngeal squamous cell carcinoma in the Chinese population.
GCST010285	Shete S	2020	394	4,493	A genome-wide association study identifies two novel susceptible regions for squamous cell carcinoma of the head and neck.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	1
Tier 3: regulatory	0
Tier 4: intronic/intergenic	7

MAF distribution

Bucket	Variants
common (>=0.05)	6
low_freq (0.01-0.05)	2
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	5
intergenic_variant	2
3_prime_UTR_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs174549	11	61803910	G>A,C,T	0.41	intron_variant	FADS1, FADS2	1e-20	Tier 4: intronic/intergenic
rs2857595	6	31600692	G>A,C,T	0.5	intergenic_variant	NCR3 - UQCRHP1	2e-15	Tier 4: intronic/intergenic
rs10492336	12	114147775	A>C,T	0.18	intron_variant	GLULP5 - LINC02459	4e-14	Tier 4: intronic/intergenic
rs142021700	18	70034347	T>C	0.01	intron_variant	RTTN	3e-09	Tier 4: intronic/intergenic
rs310518	5	83523300	G>A,T	0.21	intron_variant	VCAN	7e-08	Tier 4: intronic/intergenic
rs77045180	10	4981859	G>C,T	0.02	3_prime_UTR_variant	AKR1C1	1e-07	Tier 2: splice/UTR
rs40129	16	9344835	G>A,C,T	0.25	intron_variant	LINC02177	4e-07	Tier 4: intronic/intergenic
rs9445023	6	92812416	G>T	0.12	intergenic_variant	U3 - ATF1P1	7e-07	Tier 4: intronic/intergenic

ClinVar germline variants

4 retrieved; paginated sample, class counts are floors:

4 association

ClinVar	Variant (HGVS)	Gene	Classification	Review
2580276	NM_006297.3(XRCC1):c.*13AC[12]	XRCC1	association	no assertion criteria provided
2580277	NM_006297.3(XRCC1):c.*13AC[17]	XRCC1	association	no assertion criteria provided
2580278	NM_006297.3(XRCC1):c.839G>A (p.Arg280His)	XRCC1	association	no assertion criteria provided
2580279	NM_006297.3(XRCC1):c.602-33C>T	XRCC1	association	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 20 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
BRAF	Act	BLCA,BRCA,CHOL,CLLSLL,COAD,COADREAD,CSCC,DLBCLNOS,GBM,GIST,HGGNOS,LGGNOS,LUAD,MEL,MLYM,NSCLC,OVT,PAST,PCM,PRAD,PRCC,PROSTATE,READ,SACA,SKCM,STAD,UCEC,WDTC	CIViC #5
XRCC1			CIViC #6144
EPHA7	LoF	COADREAD,HCC,LUAD
GRIN2A	Act	BLCA,CHOL,COADREAD,MT,PANCREAS

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
TBX5	Orphanet:101016	Romano-Ward syndrome
TBX5	Orphanet:392	Holt-Oram syndrome
RTTN	Orphanet:468631	Microcephalic cortical malformations-short stature due to RTTN deficiency
VCAN	Orphanet:898	Wagner disease
GRIN2A	Orphanet:163721	Rolandic epilepsy-speech dyspraxia syndrome
GRIN2A	Orphanet:1945	Self-limited epilepsy with centrotemporal spikes
GRIN2A	Orphanet:289266	Early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation
GRIN2A	Orphanet:725	Developmental and epileptic encephalopathy with spike-wave activation in sleep
GRIN2A	Orphanet:98818	Landau-Kleffner syndrome

Cohort genes → proteins

13 cohort genes, 13 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	11
civic_only	1
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	civic_evidence
TBX5	HGNC:11604	ENSG00000089225	Q99593	T-box transcription factor TBX5	gwas
XRCC1	HGNC:12828	ENSG00000073050	P18887	DNA repair protein XRCC1	clinvar
RTTN	HGNC:18654	ENSG00000176225	Q86VV8	Rotatin	gwas
VCAN	HGNC:2464	ENSG00000038427	P13611	Versican core protein	gwas
EPHA7	HGNC:3390	ENSG00000135333	Q15375	Ephrin type-A receptor 7	gwas
AIF1	HGNC:352	ENSG00000204472	P55008	Allograft inflammatory factor 1	gwas
FADS1	HGNC:3574	ENSG00000149485	O60427	Acyl-CoA (8-3)-desaturase	gwas
FADS2	HGNC:3575	ENSG00000134824	O95864	Acyl-CoA 6-desaturase	gwas
FADS3	HGNC:3576	ENSG00000221968	Q9Y5Q0	Fatty acid desaturase 3	gwas
FEN1	HGNC:3650	ENSG00000168496	P39748	Flap endonuclease 1	gwas
AKR1C1	HGNC:384	ENSG00000187134	Q04828	Aldo-keto reductase family 1 member C1	gwas
GRIN2A	HGNC:4585	ENSG00000183454	Q12879	Glutamate receptor ionotropic, NMDA 2A	gwas

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.
TBX5	T-box transcription factor TBX5	DNA-binding protein that regulates the transcription of several genes and is involved in heart development and limb pattern formation.
XRCC1	DNA repair protein XRCC1	Scaffold protein involved in DNA single-strand break repair by mediating the assembly of DNA break repair protein complexes.
RTTN	Rotatin	Involved in the genetic cascade that governs left-right specification.
VCAN	Versican core protein	May play a role in intercellular signaling and in connecting cells with the extracellular matrix.
EPHA7	Ephrin type-A receptor 7	Receptor tyrosine kinase which binds promiscuously GPI-anchored ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells.
AIF1	Allograft inflammatory factor 1	Actin-binding protein that enhances membrane ruffling and RAC activation.
FADS1	Acyl-CoA (8-3)-desaturase	Acts as a front-end fatty acyl-coenzyme A (CoA) desaturase that introduces a cis double bond at carbon 5 located between a preexisting double bond and the carboxyl end of the fatty acyl chain.
FADS2	Acyl-CoA 6-desaturase	Involved in the biosynthesis of highly unsaturated fatty acids (HUFA) from the essential polyunsaturated fatty acids (PUFA) linoleic acid (LA) (18:2n-6) and alpha-linolenic acid (ALA) (18:3n-3) precursors, acting as a fatty acyl-coenzyme A…
FADS3	Fatty acid desaturase 3	Mammals have different sphingoid bases that differ in their length and/or pattern of desaturation and hydroxyl groups.
FEN1	Flap endonuclease 1	Structure-specific nuclease with 5’-flap endonuclease and 5’-3’ exonuclease activities involved in DNA replication and repair.
AKR1C1	Aldo-keto reductase family 1 member C1	Cytosolic aldo-keto reductase that catalyzes NADPH-dependent reduction of ketosteroids to hydroxysteroids.
GRIN2A	Glutamate receptor ionotropic, NMDA 2A	Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+).

Protein-family classification

Druggable: 8 · Difficult: 1 · Unknown: 4 · Druggable fraction: 0.62

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
Enzyme (other)	5	4.6×	0.015
Complement	1	20.6×	0.119
Kinase	2	4.3×	0.130
Transcription factor	1	0.6×	0.982
Other/Unknown	4	0.6×	0.982

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
TBX5	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
XRCC1	Other/Unknown	no		BRCT_dom, Xrcc1_N, Galactose-bd-like_sf
RTTN	Other/Unknown	no		ARM-like, ARM-type_fold, Rotatin_N
VCAN	Complement	yes		EGF-type_Asp/Asn_hydroxyl_site, Sushi_SCR_CCP_dom, Link_dom
EPHA7	Kinase	yes	2.7.10.1	Prot_kinase_dom, EPH_LBD, Ser-Thr/Tyr_kinase_cat_dom
AIF1	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, AIF1/AIF1L
FADS1	Enzyme (other)	yes	1.14.19.30	Cyt_B5-like_heme/steroid-bd, FA_desaturase_dom, Fatty_acid_desaturase
FADS2	Enzyme (other)	yes	1.14.19.3	Cyt_B5-like_heme/steroid-bd, FA_desaturase_dom, Fatty_acid_desaturase
FADS3	Enzyme (other)	yes	1.14.19.30	Cyt_B5-like_heme/steroid-bd, FA_desaturase_dom, Fatty_acid_desaturase
FEN1	Enzyme (other)	yes	3.1.99.B1	XPG/Rad2, XPG_DNA_repair_N, XPG-I_dom
AKR1C1	Enzyme (other)	yes	1.1.1.149	Aldo/ket_reductase_CS, AKR, NADP_OxRdtase_dom
GRIN2A	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt

Expression context

Cohort genes with no expression data: 0.

13 cohort genes 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)	13
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	2
tendon of biceps brachii	2
oocyte	2
leukocyte	2
monocyte	2
calcaneal tendon	1
colonic epithelium	1
cardiac muscle of right atrium	1
ganglionic eminence	1
ventricular zone	1
male germ line stem cell (sensu Vertebrata) in testis	1
secondary oocyte	1
mononuclear cell	1
cortical plate	1
lower esophagus	1
lower esophagus muscularis layer	1
granulocyte	1
superior vestibular nucleus	1
upper leg skin	1
ventral tegmental area	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
TBX5	129	broad	marker	tendon of biceps brachii, cardiac muscle of right atrium, buccal mucosa cell
XRCC1	276	ubiquitous	marker	ventricular zone, tendon of biceps brachii, ganglionic eminence
RTTN	238	ubiquitous	marker	secondary oocyte, oocyte, male germ line stem cell (sensu Vertebrata) in testis
VCAN	293	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
EPHA7	184	broad	marker	cortical plate, lower esophagus muscularis layer, lower esophagus
AIF1	159	broad	marker	monocyte, leukocyte, granulocyte
FADS1	280	ubiquitous	marker	upper leg skin, ventral tegmental area, superior vestibular nucleus
FADS2	229	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland cortex
FADS3	292	ubiquitous	marker	tibial nerve, ascending aorta, thoracic aorta
FEN1	281	ubiquitous	marker	endometrium epithelium, oocyte, cervix squamous epithelium
AKR1C1	162	ubiquitous	marker	islet of Langerhans, mucosa of stomach, right lobe of liver
GRIN2A	199	broad	marker	Brodmann (1909) area 23, endothelial cell, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BRAF	7,394
FEN1	4,897
AIF1	4,440
GRIN2A	3,146
EPHA7	2,865
VCAN	2,806
XRCC1	2,591
TBX5	2,250
RTTN	1,555
FADS1	1,423

Intra-cohort edges

A	B	Sources
FADS2	FADS3	biogrid_interaction, intact
FEN1	XRCC1	string_interaction

Structural data

PDB: 8 · AlphaFold-only: 5 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BRAF	P15056	131
GRIN2A	Q12879	37
FEN1	P39748	28
XRCC1	P18887	13
AKR1C1	Q04828	8
EPHA7	Q15375	7
TBX5	Q99593	4
AIF1	P55008	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FADS2	O95864	95.39
FADS1	O60427	94.82
FADS3	Q9Y5Q0	94.43
RTTN	Q86VV8	77.49
VCAN	P13611

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 99. Enrichment computed across 13 evidence-associated genes (10 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 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Linoleic acid (LA) metabolism	2	228.4×	0.003	FADS1, FADS2
HDR through MMEJ (alt-NHEJ)	2	175.7×	0.003	XRCC1, FEN1
alpha-linolenic acid (ALA) metabolism	2	142.8×	0.003	FADS1, FADS2
Signaling by MRAS-complex mutants	1	285.5×	0.043	BRAF
Resolution of AP sites via the single-nucleotide replacement pathway	1	228.4×	0.043	XRCC1
Signalling to p38 via RIT and RIN	1	228.4×	0.043	BRAF
Negative feedback regulation of MAPK pathway	1	190.3×	0.043	BRAF
Early Phase of HIV Life Cycle	1	163.1×	0.043	FEN1
ARMS-mediated activation	1	163.1×	0.043	BRAF
APEX1-Independent Resolution of AP Sites via the Single Nucleotide Replacement Pathway	1	163.1×	0.043	XRCC1
Prolonged ERK activation events	1	142.8×	0.043	BRAF
Defective CHST3 causes SEDCJD	1	142.8×	0.043	VCAN
Defective CHST14 causes EDS, musculocontractural type	1	142.8×	0.043	VCAN
Defective CHSY1 causes TPBS	1	142.8×	0.043	VCAN
SHOC2 M1731 mutant abolishes MRAS complex function	1	142.8×	0.043	BRAF
Gain-of-function MRAS complexes activate RAF signaling	1	142.8×	0.043	BRAF
POLB-Dependent Long Patch Base Excision Repair	1	126.9×	0.043	FEN1
Prednisone ADME	1	126.9×	0.043	AKR1C1
Signaling by FGFR3	1	114.2×	0.045	BRAF
Signaling by FGFR4	1	103.8×	0.045	BRAF
Frs2-mediated activation	1	95.2×	0.045	BRAF
DS-GAG biosynthesis	1	95.2×	0.045	VCAN
Synthesis of bile acids and bile salts via 24-hydroxycholesterol	1	87.8×	0.045	AKR1C1
Signaling by FGFR1	1	81.6×	0.045	BRAF
Removal of the Flap Intermediate	1	81.6×	0.045	FEN1
Synthesis of bile acids and bile salts via 27-hydroxycholesterol	1	76.1×	0.045	AKR1C1
YAP1- and WWTR1 (TAZ)-stimulated gene expression	1	76.1×	0.045	TBX5
Spry regulation of FGF signaling	1	71.4×	0.045	BRAF
Physiological factors	1	67.2×	0.045	TBX5
Removal of the Flap Intermediate from the C-strand	1	63.4×	0.045	FEN1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 13 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
unsaturated fatty acid biosynthetic process	3	149.6×	2e-04	FADS1, FADS2, FADS3
alpha-linolenic acid metabolic process	2	136.4×	0.010	FADS1, FADS2
linoleic acid metabolic process	2	108.0×	0.011	FADS1, FADS2
long-chain fatty acid biosynthetic process	2	68.2×	0.016	FADS1, FADS2
lipid metabolic process	3	21.1×	0.016	FADS1, FADS2, FADS3
arachidonate metabolite production involved in inflammatory response	1	1296.3×	0.017	FADS2
cell migration involved in coronary vasculogenesis	1	1296.3×	0.017	TBX5
positive regulation of cellular response to oxidative stress	1	1296.3×	0.017	FADS2
positive regulation of cardiac conduction	1	1296.3×	0.017	TBX5
visual learning	2	47.1×	0.017	BRAF, GRIN2A
cardiac left ventricle formation	1	648.1×	0.018	TBX5
negative regulation of protein ADP-ribosylation	1	648.1×	0.018	XRCC1
regulation of protein autophosphorylation	1	648.1×	0.018	EPHA7
atrioventricular node cell fate commitment	1	648.1×	0.018	TBX5
bundle of His cell to Purkinje myocyte communication by electrical coupling	1	648.1×	0.018	TBX5
positive regulation of cell communication by electrical coupling involved in cardiac conduction	1	648.1×	0.018	TBX5
regulation of base-excision repair	1	648.1×	0.018	XRCC1
atrioventricular bundle cell differentiation	1	432.1×	0.018	TBX5
parallel actin filament bundle assembly	1	432.1×	0.018	AIF1
directional locomotion	1	432.1×	0.018	GRIN2A
CD4-positive or CD8-positive, alpha-beta T cell lineage commitment	1	432.1×	0.018	BRAF
positive regulation of secondary heart field cardioblast proliferation	1	432.1×	0.018	TBX5
protein localization to postsynaptic membrane	1	432.1×	0.018	GRIN2A
bundle of His development	1	324.1×	0.018	TBX5
DNA replication, removal of RNA primer	1	324.1×	0.018	FEN1
positive regulation of cardioblast differentiation	1	324.1×	0.018	TBX5
atrioventricular node cell development	1	324.1×	0.018	TBX5
telomeric DNA-containing double minutes formation	1	324.1×	0.018	XRCC1
cellular response to jasmonic acid stimulus	1	324.1×	0.018	AKR1C1
negative regulation of smooth muscle cell chemotaxis	1	324.1×	0.018	AIF1

Therapeutics

Drugs indicated for this disease

1 approved, 4 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Pembrolizumab	Approved (phase 4)
Carboplatin	Phase 3 (in late-stage trials)
Cetuximab	Phase 3 (in late-stage trials)
Cisplatin	Phase 3 (in late-stage trials)
Paclitaxel	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Capecitabine, Ixabepilone, Trastuzumab.

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 4 · Phased (≥1): 4 · Undrugged: 9

Druggability breadth: 8 of 13 evidence-associated genes (62%) 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
EPHA7	FEDRATINIB
AKR1C1	DIAZEPAM
GRIN2A	MEMANTINE HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BRAF	48	4
GRIN2A	37	4
EPHA7	29	4
AKR1C1	9	4
TBX5	0	0
XRCC1	0	0
RTTN	0	0
VCAN	0	0
AIF1	0	0
FADS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	BRAF
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF, EPHA7
SORAFENIB	4	BRAF, EPHA7
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, EPHA7
GEFITINIB	4	BRAF
IMATINIB	4	BRAF
VANDETANIB	4	EPHA7
GILTERITINIB	4	EPHA7
SUNITINIB	4	EPHA7
QUIZARTINIB	4	EPHA7
CRIZOTINIB	4	EPHA7
DIAZEPAM	4	AKR1C1
GLIMEPIRIDE	4	AKR1C1
BENZBROMARONE	4	AKR1C1
MECLOFENAMIC ACID	4	AKR1C1
FLURBIPROFEN	4	AKR1C1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

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

Symbol	Assays	Type breakdown
BRAF	1,442	Binding:1400, Functional:37, ADMET:5
GRIN2A	324	Binding:296, Functional:23, ADMET:4, Toxicity:1
EPHA7	231	Binding:231
AKR1C1	100	Binding:91, ADMET:9
FADS1	21	Binding:21
FEN1	15	Binding:12, Functional:3
FADS2	11	Binding:11
TBX5	1	Binding:1

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
EPHA7	2.7.10.1	receptor protein-tyrosine kinase
FADS1	1.14.19.30	acyl-lipid (8-3)-desaturase
FADS2	1.14.19.3	acyl-CoA 6-desaturase
FADS3	1.14.19.30	acyl-lipid (8-3)-desaturase
FEN1	3.1.99.B1
AKR1C1	1.1.1.149, 1.1.1.270, 1.1.1.357, 1.1.1.50, 1.3.1.20	20alpha-hydroxysteroid dehydrogenase, 3beta-hydroxysteroid 3-dehydrogenase, 3alpha-hydroxysteroid 3-dehydrogenase, 3alpha-hydroxysteroid 3-dehydrogenase (Si-specific), trans-1,2-dihydrobenzene-1,2-diol dehydrogenase

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
EPHA7	231
AKR1C1	100
GRIN2A	324

Pharmacogenomics

Cohort genes with a PharmGKB record: 13; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

28 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

Compound	Max phase	Cohort target (bioactivity)
VEMURAFENIB	4	BRAF
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF, EPHA7
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, EPHA7
GEFITINIB	4	BRAF
IMATINIB	4	BRAF
VANDETANIB	4	EPHA7
GILTERITINIB	4	EPHA7
SUNITINIB	4	EPHA7
QUIZARTINIB	4	EPHA7
CRIZOTINIB	4	EPHA7
DIAZEPAM	4	AKR1C1
GLIMEPIRIDE	4	AKR1C1
BENZBROMARONE	4	AKR1C1
MECLOFENAMIC ACID	4	AKR1C1
FLURBIPROFEN	4	AKR1C1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	BRAF, EPHA7, AKR1C1, GRIN2A
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	FEN1
D	Druggable family + AlphaFold only, no drug	4	VCAN, FADS1, FADS2, FADS3
E	Difficult family or no structure, no drug	4	TBX5, XRCC1, RTTN, AIF1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TBX5	1	—
XRCC1	0	—
RTTN	0	—
VCAN	0	—
AIF1	0	—
FADS1	21	—
FADS2	11	—
FADS3	0	—
FEN1	15	—

Clinical trials & evidence

Clinical trials

Clinical trials: 132.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	56
PHASE1	37
Not specified	18
PHASE1/PHASE2	8
PHASE3	5
PHASE2/PHASE3	5
EARLY_PHASE1	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00588770	PHASE3	ACTIVE_NOT_RECRUITING	Chemotherapy With or Without Bevacizumab in Treating Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
NCT01810913	PHASE2/PHASE3	RECRUITING	Testing Docetaxel-Cetuximab or the Addition of an Immunotherapy Drug, Atezolizumab, to the Usual Chemotherapy and Radiation Therapy in High-Risk Head and Neck Cancer
NCT05063552	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Testing the Use of Investigational Drugs Atezolizumab and/or Bevacizumab With or Without Standard Chemotherapy in the Second-Line Treatment of Advanced-Stage Head and Neck Cancers
NCT05333523	PHASE3	RECRUITING	Personalized Elective Neck Irradiation Guided by Sentinel Lymph Node Biopsy in Larynx and Pharynx Cancer. The PRIMO Study.
NCT05721755	PHASE3	ACTIVE_NOT_RECRUITING	Combining Radiation Therapy With Immunotherapy for the Treatment of Metastatic Squamous Cell Carcinoma of the Head and Neck
NCT06030440	PHASE2/PHASE3	RECRUITING	De-Intensification of Postoperative Radiotherapy in Patients With Squamous Cell Carcinoma of the Head and Neck
NCT06589804	PHASE3	RECRUITING	Testing the Addition of Anti-Cancer Drug, Cetuximab, to Standard of Care Treatment (Pembrolizumab) for Returning or Spreading Head and Neck Cancer After Previous Treatment
NCT02236936	PHASE3	TERMINATED	Parenteral Nutrition for Patients Treated for Locally Advanced Inoperable Tumors of the Head and Neck
NCT03258554	PHASE2/PHASE3	COMPLETED	Radiation Therapy With Durvalumab or Cetuximab in Treating Patients With Locoregionally Advanced Head and Neck Cancer Who Cannot Take Cisplatin
NCT05050162	PHASE2/PHASE3	SUSPENDED	Comparing Cisplatin Every Three Weeks to Cisplatin Weekly When Combined With Radiation for Patients With Advanced Head and Neck Cancer
NCT00494182	PHASE2	ACTIVE_NOT_RECRUITING	Sorafenib in Combination With Carboplatin and Paclitaxel in Treating Participants With Metastatic or Recurrent Head and Neck Squamous Cell Cancer
NCT02734537	PHASE2	RECRUITING	Radiation Therapy With or Without Cisplatin in Treating Patients With Stage III-IVA Squamous Cell Carcinoma of the Head and Neck Who Have Undergone Surgery
NCT03468218	PHASE2	ACTIVE_NOT_RECRUITING	Pembrolizumab & Cabozantinib in Patients With Head and Neck Squamous Cell Cancer
NCT04030455	PHASE2	ACTIVE_NOT_RECRUITING	Cisplatin, Docetaxel, and Pembrolizumab in Treating Patients With Stage II-III Laryngeal Cancer
NCT04671667	PHASE2	RECRUITING	Testing What Happens When an Immunotherapy Drug (Pembrolizumab) is Given by Itself Compared to the Usual Treatment of Chemotherapy With Radiation After Surgery for Recurrent Head and Neck Squamous Cell Carcinoma
NCT04858269	PHASE2	ACTIVE_NOT_RECRUITING	First Line Weekly Chemo/Immunotherapy for Metastatic Head/Neck Squamous Cell Carcinoma Patients
NCT04862650	PHASE2	ACTIVE_NOT_RECRUITING	Cemiplimab, Low-Dose Paclitaxel and Carboplatin for the Treatment of Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck
NCT04943445	PHASE2	ACTIVE_NOT_RECRUITING	Study of a Pembrolizumab-based Organ Preservation Strategy for Locally Advanced Larynx Cancers
NCT05136196	PHASE2	RECRUITING	BiCaZO: A Study Combining Two Immunotherapies (Cabozantinib and Nivolumab) to Treat Patients With Advanced Melanoma or Squamous Cell Head and Neck Cancer, an immunoMATCH Pilot Study
NCT05144698	PHASE1/PHASE2	RECRUITING	RAPA-201 Therapy of Solid Tumors
NCT05172258	PHASE2	ACTIVE_NOT_RECRUITING	Testing the Addition of an Anti-cancer Drug, Ipatasertib, to the Usual Immunotherapy Treatment (Pembrolizumab) in Patients With Recurrent or Metastatic Squamous Cell Cancer of the Head and Neck
NCT05752149	PHASE2	NOT_YET_RECRUITING	Fluorescence-guided Surgery in Laryngeal- and Hypopharyngeal Cancer: a Feasibility Trial
NCT06137378	PHASE2	RECRUITING	European Larynx Organ Preservation Study (ELOS) [MK-3475-C44]
NCT06532279	PHASE2	RECRUITING	Testing the Addition of the Drug BMX-001, a Radioprotector, or a Placebo to the Usual Chemoradiation Therapy for Patients With Head and Neck Cancer
NCT06636734	PHASE2	RECRUITING	Lovastatin and Pembrolizumab for the Treatment of Patients With Recurrent or Metastatic Head and Neck Cancer, LAPP Trial
NCT06980038	PHASE2	RECRUITING	Testing Whether Cemiplimab (REGN2810) Plus CDX-1140 Given Prior to Surgery Are Better Than Cemiplimab (REGN2810) Alone in Patients With Stage III-IV Head and Neck Cancer
NCT07058805	PHASE2	RECRUITING	Compartmentalized Postoperative Radiotherapy in Head and Neck Cancer
NCT07063212	PHASE2	RECRUITING	A Study of Sacituzumab Govitecan in Combination With Cetuximab in People With Head and Neck Squamous Cell Cancer (HNSCC)
NCT07392580	PHASE2	NOT_YET_RECRUITING	Intralesional Chemotherapy (IC): Cisplatin + Epinephrine
NCT07423078	PHASE2	RECRUITING	Window of Opportunity in Preserving Laryngeal Function Trial
NCT00033618	PHASE2	COMPLETED	Ixabepilone in Treating Patients With Metastatic or Recurrent Squamous Cell Cancer of the Head and Neck
NCT00055770	PHASE1/PHASE2	COMPLETED	Erlotinib Plus Docetaxel in Treating Patients With Locally Advanced, Metastatic, or Recurrent Head and Neck Cancer
NCT00055913	PHASE1/PHASE2	COMPLETED	Bevacizumab and Erlotinib in Treating Patients With Recurrent or Metastatic Head and Neck Cancer
NCT00063895	PHASE1/PHASE2	COMPLETED	Erlotinib in Treating Patients With Advanced Non-Small Cell Lung Cancer, Ovarian Cancer, or Squamous Cell Carcinoma of the Head and Neck
NCT00084682	PHASE2	COMPLETED	Depsipeptide in Unresectable Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck
NCT00095628	PHASE2	COMPLETED	SB-715992 in Treating Patients With Recurrent or Metastatic Head and Neck Cancer
NCT00095641	PHASE2	WITHDRAWN	S0225 Capecitabine in Treating Patients Who Have Undergone Surgery for Locally Recurrent or Persistent Head and Neck Cancer
NCT00096512	PHASE2	COMPLETED	S0420, Sorafenib in Treating Patients With Recurrent or Metastatic Head and Neck Cancer
NCT00098631	PHASE2	COMPLETED	Lapatinib in Treating Patients With Recurrent and/or Metastatic Head and Neck Cancer
NCT00101348	PHASE1/PHASE2	COMPLETED	Erlotinib and Cetuximab With or Without Bevacizumab in Treating Patients With Metastatic or Unresectable Kidney, Colorectal, Head and Neck, Pancreatic, or Non-Small Cell Lung Cancer

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CISPLATIN	4	29
LAPATINIB	4	6
CETUXIMAB	4	5
ERLOTINIB HYDROCHLORIDE	4	5
SORAFENIB	4	4
ATEZOLIZUMAB	4	2
DASATINIB ANHYDROUS	4	2
DURVALUMAB	4	1
FOSAPREPITANT DIMEGLUMINE	4	1
IXABEPILONE	4	1
PALONOSETRON HYDROCHLORIDE	4	1
PORFIMER SODIUM	4	1
ROMIDEPSIN	4	1
SELENOMETHIONINE	4	1
SUNITINIB MALATE	4	1
TEMSIROLIMUS	4	1
VORINOSTAT	4	1
CEDIRANIB MALEATE	3	1
SARACATINIB	3	1
ISPINESIB	2	1
SOY ISOFLAVONES	2	1
CHEMBL5412235	0	2
CHEMBL4066465	0	1
CHEMBL2326523	0	1
CHEMBL3109278	0	1
CHEMBL4583196	0	1
CHEMBL4438584	0	1
CHEMBL1474517	0	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 1 predictive associations from 1 curated evidence items.

Molecular subtype	Therapy	Effect	Level	CIViC
BRAF V600E	Vemurafenib	Sensitivity/Response	CIViC C	EID5962