Colorectal adenocarcinoma

Summary

Colorectal adenocarcinoma (MONDO:0005008) is a disease (an umbrella term covering 5 Mondo subtypes) with 8 cohort genes (1 GWAS associations across 1 studies) and 147 clinical trials. Molecularly, BRAF V600E confers sensitivity to Trametinib + Panitumumab in Colorectal Adenocarcinoma (CIViC Level B); 17 further subtype–drug associations are mapped below. Top therapeutic interventions include bevacizumab, tipiracil, and trifluridine.

At a glance

• Umbrella term: 5 Mondo subtypes
• Cohort genes: 8
• GWAS associations: 1
• Clinical trials: 147
• Precision-medicine evidence (CIViC): 18 subtype–drug associations

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	colorectal adenocarcinoma
Mondo ID	MONDO:0005008
EFO	EFO:0000365
DOID	DOID:0050861, DOID:0050913
NCIT	C5105
SNOMED CT	408645001
UMLS	C1319315
MedGen	230816
Anatomy (UBERON)	UBERON:0012652
Is cancer (heuristic)	no

Also known as: adenocarcinoma of large bowel · adenocarcinoma of large intestine · adenocarcinoma of the large bowel · adenocarcinoma of the large intestine · colorectal (colon or rectal) adenocarcinoma · colorectal adenocarcinoma · colorectum adenocarcinoma · large bowel adenocarcinoma

Data availability: 1 GWAS association (1 study) · 22 cell lines · 82 intOGen driver records.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › cancer › carcinoma › adenocarcinoma › colorectal adenocarcinoma

Related subtypes (63): epididymal adenocarcinoma, rete testis adenocarcinoma, seminal vesicle adenocarcinoma, ethmoid sinus adenocarcinoma, lacrimal gland adenocarcinoma, papillary adenocarcinoma, fallopian tube adenocarcinoma, bladder adenocarcinoma, ovarian adenocarcinoma, trabecular adenocarcinoma, middle ear adenocarcinoma, bile duct adenocarcinoma, granular cell carcinoma, small intestine adenocarcinoma, urethra adenocarcinoma, villous adenocarcinoma, thymus gland adenocarcinoma, nasal cavity adenocarcinoma, ureter adenocarcinoma, adenocarcinoma in situ, gastroesophageal junction adenocarcinoma, maxillary sinus adenocarcinoma, mucinous adenocarcinoma, acinar cell carcinoma, adenoid cystic carcinoma, breast adenocarcinoma, clear cell adenocarcinoma, endometrioid adenocarcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, lung adenocarcinoma, prostate adenocarcinoma, renal cell carcinoma, signet ring cell carcinoma, cervical adenocarcinoma, serous adenocarcinoma, endometrium adenocarcinoma, sweat gland carcinoma, cystadenocarcinoma, tubular adenocarcinoma, mesonephric adenocarcinoma, scirrhous adenocarcinoma, pancreatic adenocarcinoma, follicular variant thyroid gland papillary carcinoma, gallbladder adenocarcinoma, hepatoid adenocarcinoma, intestinal type adenocarcinoma, micropapillary serous carcinoma, minor salivary gland adenocarcinoma, poorly differentiated thyroid gland carcinoma, salivary gland basal cell adenocarcinoma, submandibular gland adenocarcinoma, sebaceous adenocarcinoma, hepatocellular carcinoma, parathyroid gland carcinoma, pituitary adenocarcinoma, vaginal adenocarcinoma, Paget disease, diffuse type adenocarcinoma, vulvar adenocarcinoma, thyroid gland adenocarcinoma, gastroesophageal adenocarcinoma, adenoacanthoma

Subtypes (5): rectum adenocarcinoma, colon adenocarcinoma, colorectal serrated adenocarcinoma, colorectal medullary carcinoma, colorectal signet ring cell carcinoma

Genetics & variants

GWAS landscape

1 GWAS associations across 1 studies. Top hits map to 1 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs4939827	2e-10	SMAD7	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST010992	Campbell PT	2020	14,059	14,416	Association of body mass index with colorectal cancer risk by genome-wide variants.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

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

MAF distribution

Bucket	Variants
common (>=0.05)	1
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs4939827	18	48927093	T>A,C	0.05	intron_variant	SMAD7	2e-10	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 53 · 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
TP53	Orphanet:1333	Familial pancreatic carcinoma
TP53	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
TP53	Orphanet:1501	Adrenocortical carcinoma
TP53	Orphanet:210159	Adult hepatocellular carcinoma
TP53	Orphanet:251576	Gliosarcoma
TP53	Orphanet:251579	Giant cell glioblastoma
TP53	Orphanet:251899	Choroid plexus carcinoma
TP53	Orphanet:2807	Papilloma of choroid plexus
TP53	Orphanet:293199	Pleomorphic rhabdomyosarcoma
TP53	Orphanet:3318	Essential thrombocythemia
TP53	Orphanet:524	Li-Fraumeni syndrome
TP53	Orphanet:52688	Myelodysplastic syndrome
TP53	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
TP53	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
TP53	Orphanet:668	Osteosarcoma
TP53	Orphanet:67038	B-cell chronic lymphocytic leukemia
TP53	Orphanet:70573	Small cell lung cancer
TP53	Orphanet:96253	Cushing disease
TP53	Orphanet:99756	Alveolar rhabdomyosarcoma
TP53	Orphanet:99757	Embryonal rhabdomyosarcoma
ERBB2	Orphanet:213726	Serous carcinoma of the corpus uteri
ERBB2	Orphanet:2800	Extramammary Paget disease
ERBB2	Orphanet:388	Hirschsprung disease
ERBB2	Orphanet:99976	Adenocarcinoma of the oesophagus and oesophagogastric junction
KDR	Orphanet:3303	Tetralogy of Fallot
KRAS	Orphanet:1333	Familial pancreatic carcinoma
KRAS	Orphanet:1340	Cardiofaciocutaneous syndrome
KRAS	Orphanet:144	Lynch syndrome
KRAS	Orphanet:146	Differentiated thyroid carcinoma
KRAS	Orphanet:2396	Encephalocraniocutaneous lipomatosis
KRAS	Orphanet:251615	Pilomyxoid astrocytoma
KRAS	Orphanet:2612	Linear nevus sebaceus syndrome
KRAS	Orphanet:268114	RAS-associated autoimmune leukoproliferative disease
KRAS	Orphanet:3339	Oculoectodermal syndrome
KRAS	Orphanet:648	Noonan syndrome
KRAS	Orphanet:86834	Juvenile myelomonocytic leukemia
KMT2D	Orphanet:2322	Kabuki syndrome
KMT2D	Orphanet:589856	Choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome
NTRK1	Orphanet:146	Differentiated thyroid carcinoma

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
civic_only	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	civic_evidence
TP53	HGNC:11998	ENSG00000141510	P04637	Cellular tumor antigen p53	civic_evidence
ERBB2	HGNC:3430	ENSG00000141736	P04626	Receptor tyrosine-protein kinase erbB-2	civic_evidence
JUN	HGNC:6204	ENSG00000177606	P05412	Transcription factor Jun	civic_evidence
KDR	HGNC:6307	ENSG00000128052	P35968	Vascular endothelial growth factor receptor 2	civic_evidence
KRAS	HGNC:6407	ENSG00000133703	P01116	GTPase KRas	civic_evidence
KMT2D	HGNC:7133	ENSG00000167548	O14686	Histone-lysine N-methyltransferase 2D	civic_evidence
NTRK1	HGNC:8031	ENSG00000198400	P04629	High affinity nerve growth factor receptor	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.
TP53	Cellular tumor antigen p53	Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence.
ERBB2	Receptor tyrosine-protein kinase erbB-2	Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding.
JUN	Transcription factor Jun	Transcription factor that recognizes and binds to the AP-1 consensus motif 5’-TGA[GC]TCA-3'.
KDR	Vascular endothelial growth factor receptor 2	Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD.
KRAS	GTPase KRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
KMT2D	Histone-lysine N-methyltransferase 2D	Histone methyltransferase that catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of ‘Lys-4’ of histone H3 (H3K4).
NTRK1	High affinity nerve growth factor receptor	Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons.

Protein-family classification

Druggable: 5 · Difficult: 3 · Unknown: 0 · 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
Kinase	4	13.9×	3e-04
Transcription factor	3	3.1×	0.093
Enzyme (other)	1	1.5×	0.502

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
TP53	Transcription factor	no		p53_tumour_suppressor, p53-like_TF_DNA-bd_sf, p53_tetrameristn
ERBB2	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
JUN	Transcription factor	no		Leuzip_Jun, bZIP, JNK
KDR	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_rcpt_3_CS
KRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
KMT2D	Transcription factor	no		SET_dom, Znf_RING, Znf_PHD
NTRK1	Kinase	yes	2.7.10.1	Cys-rich_flank_reg_C, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom

Expression context

Cohort genes with no expression data: 0.

8 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	2
sural nerve	2
calcaneal tendon	1
colonic epithelium	1
ganglionic eminence	1
tendon of biceps brachii	1
ventricular zone	1
lower esophagus mucosa	1
right uterine tube	1
cardia of stomach	1
mucosa of stomach	1
vena cava	1
germinal epithelium of ovary	1
lower lobe of lung	1
parietal pleura	1
nipple	1
pylorus	1
trigeminal ganglion	1
medial globus pallidus	1
apex of heart	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
TP53	223	ubiquitous	marker	ventricular zone, ganglionic eminence, tendon of biceps brachii
ERBB2	276	ubiquitous	marker	lower esophagus mucosa, right uterine tube, sural nerve
JUN	290	ubiquitous	marker	vena cava, mucosa of stomach, cardia of stomach
KDR	267	broad	marker	germinal epithelium of ovary, lower lobe of lung, parietal pleura
KRAS	298	ubiquitous	marker	trigeminal ganglion, pylorus, nipple
KMT2D	272	ubiquitous	marker	buccal mucosa cell, medial globus pallidus, sural nerve
NTRK1	160	broad	marker	dorsal root ganglion, apex of heart, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TP53	22,736
KRAS	14,509
JUN	12,228
ERBB2	9,659
NTRK1	9,181
BRAF	7,394
KDR	4,960
KMT2D	3,223

Intra-cohort edges

A	B	Sources
BRAF	KRAS	biogrid_interaction, intact, string_interaction
BRAF	TP53	string_interaction
ERBB2	KRAS	string_interaction
JUN	TP53	string_interaction
KMT2D	TP53	string_interaction
KRAS	TP53	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRAS	P01116	511
TP53	P04637	313
BRAF	P15056	131
NTRK1	P04629	65
ERBB2	P04626	63
KDR	P35968	54
KMT2D	O14686	11
JUN	P05412	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 256. Enrichment computed across 8 evidence-associated genes (8 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 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signalling to p38 via RIT and RIN	2	571.0×	0.001	BRAF, NTRK1
ARMS-mediated activation	2	407.9×	0.001	BRAF, NTRK1
Frs2-mediated activation	2	237.9×	0.002	BRAF, NTRK1
Constitutive Signaling by Overexpressed ERBB2	2	237.9×	0.002	ERBB2, KRAS
Signalling to RAS	2	167.9×	0.002	KRAS, NTRK1
Signaling by ERBB2 ECD mutants	2	167.9×	0.002	ERBB2, KRAS
GRB2 events in ERBB2 signaling	2	158.6×	0.002	ERBB2, KRAS
VEGFR2 mediated cell proliferation	2	142.8×	0.003	KDR, KRAS
SHC1 events in ERBB2 signaling	2	119.0×	0.003	ERBB2, KRAS
Signaling by ERBB2 TMD/JMD mutants	2	119.0×	0.003	ERBB2, KRAS
Activation of HOX genes during differentiation	2	109.8×	0.003	JUN, KMT2D
Signaling by ERBB2 KD Mutants	2	105.7×	0.003	ERBB2, KRAS
FCERI mediated MAPK activation	2	86.5×	0.004	JUN, KRAS
RAF activation	2	84.0×	0.004	BRAF, KRAS
RAF/MAP kinase cascade	3	22.9×	0.004	BRAF, ERBB2, KRAS
Signaling by high-kinase activity BRAF mutants	2	79.3×	0.004	BRAF, KRAS
MAP2K and MAPK activation	2	71.4×	0.005	BRAF, KRAS
Signaling by RAF1 mutants	2	69.6×	0.005	BRAF, KRAS
Negative regulation of MAPK pathway	2	66.4×	0.005	BRAF, KRAS
Signaling by moderate kinase activity BRAF mutants	2	63.4×	0.005	BRAF, KRAS
Paradoxical activation of RAF signaling by kinase inactive BRAF	2	63.4×	0.005	BRAF, KRAS
Signaling downstream of RAS mutants	2	63.4×	0.005	BRAF, KRAS
Loss of function of TP53 in cancer due to loss of tetramerization ability	1	1427.5×	0.008	TP53
TP53 Regulates Transcription of DNA Repair Genes	2	45.3×	0.009	TP53, JUN
Regulation of PTEN gene transcription	2	44.6×	0.009	TP53, JUN
Signaling by BRAF and RAF1 fusions	2	42.6×	0.009	BRAF, KRAS
Signaling by ALK fusions and activated point mutants	2	37.6×	0.011	TP53, JUN
TRKA activation by NGF	1	713.8×	0.012	NTRK1
Regulation of TP53 Expression	1	713.8×	0.012	TP53
Killing mechanisms	1	713.8×	0.012	JUN

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of neuron apoptotic process	5	69.3×	1e-06	BRAF, JUN, KDR, KRAS, NTRK1
peptidyl-tyrosine phosphorylation	3	158.0×	1e-04	ERBB2, KDR, NTRK1
positive regulation of ERK1 and ERK2 cascade	4	42.6×	1e-04	BRAF, JUN, KDR, NTRK1
neuron apoptotic process	3	69.5×	7e-04	TP53, KRAS, NTRK1
cell surface receptor protein tyrosine kinase signaling pathway	3	65.2×	7e-04	ERBB2, KDR, NTRK1
positive regulation of cellular senescence	2	324.1×	8e-04	TP53, KRAS
glial cell proliferation	2	221.7×	0.002	TP53, KRAS
negative regulation of apoptotic process	4	17.4×	0.002	BRAF, TP53, ERBB2, NTRK1
negative regulation of endothelial cell apoptotic process	2	123.9×	0.004	BRAF, KDR
T cell differentiation in thymus	2	102.8×	0.005	BRAF, TP53
semaphorin-plexin signaling pathway	2	100.3×	0.005	ERBB2, KDR
protein phosphorylation	3	25.5×	0.005	BRAF, ERBB2, NTRK1
negative regulation of helicase activity	1	2106.5×	0.007	TP53
response to mineralocorticoid	1	2106.5×	0.007	KRAS
cellular response to actinomycin D	1	2106.5×	0.007	TP53
positive regulation of nitric oxide-cGMP mediated signal transduction	1	2106.5×	0.007	KDR
regulation of intrinsic apoptotic signaling pathway by p53 class mediator	1	2106.5×	0.007	TP53
negative regulation of G1 to G0 transition	1	2106.5×	0.007	TP53
beta-catenin-TCF complex assembly	1	2106.5×	0.007	KMT2D
stem cell proliferation	2	78.0×	0.007	TP53, KDR
visual learning	2	76.6×	0.007	BRAF, KRAS
positive regulation of miRNA transcription	2	72.6×	0.007	TP53, JUN
epidermal growth factor receptor signaling pathway	2	62.0×	0.007	BRAF, ERBB2
cellular response to xenobiotic stimulus	2	60.2×	0.007	BRAF, TP53
positive regulation of endothelial cell proliferation	2	57.7×	0.007	JUN, KDR
liver development	2	55.4×	0.007	JUN, KRAS
Ras protein signal transduction	2	51.4×	0.008	TP53, KRAS
cellular response to calcium ion	2	50.1×	0.008	BRAF, JUN
negative regulation of cell population proliferation	3	15.8×	0.008	TP53, JUN, NTRK1
programmed cell death involved in cell development	1	1053.2×	0.009	NTRK1

Therapeutics

Drugs indicated for this disease

11 approved, 28 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Aflibercept	Approved (phase 4)
Bevacizumab	Approved (phase 4)
Capecitabine	Approved (phase 4)
Cetuximab	Approved (phase 4)
Encorafenib	Approved (phase 4)
Fruquintinib	Approved (phase 4)
Ipilimumab	Approved (phase 4)
Nivolumab	Approved (phase 4)
Panitumumab	Approved (phase 4)
Regorafenib	Approved (phase 4)
Trifluridine	Approved (phase 4)
Ascorbic Acid	Phase 3 (in late-stage trials)
Bermekimab	Phase 3 (in late-stage trials)
Celecoxib	Phase 3 (in late-stage trials)
Cholecalciferol	Phase 3 (in late-stage trials)
Cisplatin	Phase 3 (in late-stage trials)
Dexamethasone	Phase 3 (in late-stage trials)
Eniluracil	Phase 3 (in late-stage trials)
Famitinib	Phase 3 (in late-stage trials)
Floxuridine	Phase 3 (in late-stage trials)
Fluorouracil	Phase 3 (in late-stage trials)
Gimeracil	Phase 3 (in late-stage trials)
Glutamine	Phase 3 (in late-stage trials)
Heparin	Phase 3 (in late-stage trials)
Irinotecan	Phase 3 (in late-stage trials)
Metformin	Phase 3 (in late-stage trials)
Metronidazole	Phase 3 (in late-stage trials)
Nintedanib	Phase 3 (in late-stage trials)
Oteracil	Phase 3 (in late-stage trials)
Oxaliplatin	Phase 3 (in late-stage trials)
Pembrolizumab	Phase 3 (in late-stage trials)
Raltitrexed	Phase 3 (in late-stage trials)
Relatlimab	Phase 3 (in late-stage trials)
Rivoceranib	Phase 3 (in late-stage trials)
Semaxanib	Phase 3 (in late-stage trials)
Sintilimab	Phase 3 (in late-stage trials)
Tegafur	Phase 3 (in late-stage trials)
Thalidomide	Phase 3 (in late-stage trials)
Tinzaparin	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): ANTINEOPLASTON A10, Avelumab, Avutometinib, Bintrafusp Alfa, Brivanib, Cabozantinib, Cadonilimab, Camrelizumab, Clobetasol Propionate, Durvalumab, Enzastaurin, Erythromycin, Everolimus, Gemcitabine, Lapatinib, Linifanib, Niraparib, Nogapendekin Alfa, Paclitaxel, Pertuzumab, Pexastimogene Devacirepvec, Recombinant Human Thrombopoietin, Regramostim, Saracatinib, Selenomethionine, Temozolomide, Tislelizumab, Trametinib, Tremelimumab, Vandetanib, Vemurafenib, Vorinostat.

Drug target analysis

Approved (phase 4): 6 · Phase ≥3: 7 · Phased (≥1): 7 · Undrugged: 1

Druggability breadth: 8 of 8 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
TP53	NITROFURANTOIN
ERBB2	CLOTRIMAZOLE
KDR	VANDETANIB
KRAS	VEMURAFENIB
NTRK1	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TP53	196	4
KDR	172	4
ERBB2	83	4
NTRK1	66	4
BRAF	48	4
KRAS	11	4
JUN	3	3
KMT2D	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	BRAF, KDR, KRAS
PONATINIB	4	BRAF, ERBB2, KDR, NTRK1
FEDRATINIB	4	BRAF, KDR, NTRK1
SORAFENIB	4	BRAF, ERBB2, KDR, NTRK1
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF, NTRK1
INFIGRATINIB PHOSPHATE	4	BRAF, KDR
INFIGRATINIB	4	BRAF, KDR
REGORAFENIB	4	BRAF, KDR
DABRAFENIB	4	BRAF, KRAS
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF, KDR, NTRK1
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF, KDR
DASATINIB	4	BRAF, ERBB2, KDR
ERLOTINIB	4	BRAF, ERBB2, KDR
GEFITINIB	4	BRAF, ERBB2, KDR
IMATINIB	4	BRAF, ERBB2, KDR
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	ERBB2, TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	TP53

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 5.

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

Symbol	Assays	Type breakdown
KDR	2,687	Binding:2594, Functional:64, ADMET:27, Toxicity:2
BRAF	1,442	Binding:1400, Functional:37, ADMET:5
ERBB2	1,221	Binding:1136, Functional:79, ADMET:6
NTRK1	1,194	Binding:1182, ADMET:7, Functional:5
TP53	869	Binding:775, ADMET:83, Functional:10, Toxicity:1
KRAS	861	Binding:829, Functional:32
JUN	88	Binding:87, Functional:1
KMT2D	11	Binding:11

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
ERBB2	2.7.10.1	receptor protein-tyrosine kinase
KDR	2.7.10.1	receptor protein-tyrosine kinase
KRAS	3.6.5.2	small monomeric GTPase
NTRK1	2.7.10.1	receptor protein-tyrosine 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
TP53	869
ERBB2	1,221
KDR	2,687
KRAS	861
NTRK1	1,194

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

28 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)
VEMURAFENIB	4	BRAF, KDR, KRAS
PONATINIB	4	BRAF, ERBB2, KDR, NTRK1
FEDRATINIB	4	BRAF, KDR, NTRK1
SORAFENIB	4	BRAF, ERBB2, KDR, NTRK1
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF, NTRK1
INFIGRATINIB PHOSPHATE	4	BRAF, KDR
INFIGRATINIB	4	BRAF, KDR
DABRAFENIB	4	BRAF, KRAS
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF, KDR, NTRK1
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF, KDR
DASATINIB	4	BRAF, ERBB2, KDR
ERLOTINIB	4	BRAF, ERBB2, KDR
GEFITINIB	4	BRAF, ERBB2, KDR
IMATINIB	4	BRAF, ERBB2, KDR
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	ERBB2, TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	TP53

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	6	BRAF, TP53, ERBB2, KDR, KRAS, NTRK1
B	Phased (≥1) drug, not yet approved	1	JUN
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	KMT2D

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KMT2D	11	—

Clinical trials & evidence

Clinical trials

Clinical trials: 147.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	46
Not specified	46
PHASE1	25
PHASE1/PHASE2	23
PHASE3	6
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02758951	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Perioperative Systemic Therapy for Isolated Resectable Colorectal Peritoneal Metastases
NCT02997228	PHASE3	ACTIVE_NOT_RECRUITING	Testing the Addition of Atezolizumab to Combination Chemotherapy or Atezolizumab Alone for Metastatic Colon or Rectal Cancer, the COMMIT Study
NCT04094688	PHASE3	ACTIVE_NOT_RECRUITING	Vitamin D3 With Chemotherapy and Bevacizumab in Treating Patients With Advanced or Metastatic Colorectal Cancer
NCT05673148	PHASE3	RECRUITING	Testing the Addition of Total Ablative Therapy to Usual Systemic Therapy Treatment for Limited Metastatic Colorectal Cancer, The ERASur Study
NCT06951503	PHASE3	RECRUITING	AK112 and Chemotherapy in First-line Metastatic Colorectal Cancer
NCT03300609	PHASE3	TERMINATED	5-FU Based Maintenance Therapy in RAS Wild Type Metastatic Colorectal Cancer After Induction With FOLFOX Plus Panitumumab
NCT03708536	PHASE3	WITHDRAWN	Bevacizumab Plus Capecitabin vs S-1 as Maintenance Treatment Following First-line Chemotherapy in the Patients With Advanced Colorectal Adenocarcinoma
NCT03087071	PHASE2	ACTIVE_NOT_RECRUITING	Panitumumab With or Without Trametinib in Treating Patients With Stage IV Colorectal Cancer
NCT03368963	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	TAS102 in Combination With NAL-IRI in Advanced GI Cancers
NCT03599752	PHASE2	ACTIVE_NOT_RECRUITING	Chemotherapy and/or Metastasectomy in Treating Patients With Metastatic Colorectal Adenocarcinoma With Lung Metastases
NCT04111172	PHASE2	ACTIVE_NOT_RECRUITING	A Vaccine (Ad5.F35-hGCC-PADRE) for the Treatment of Gastrointestinal Adenocarcinoma
NCT04117945	PHASE2	ACTIVE_NOT_RECRUITING	Regorafenib, With Cetuximab or Panitumumab, for the Treatment of Unresectable, Locally Advanced, or Metastatic Colorectal Cancer
NCT04457284	PHASE2	ACTIVE_NOT_RECRUITING	Temozolomide, Cisplatin, and Nivolumab in People With Colorectal Cancer
NCT04729322	PHASE2	ACTIVE_NOT_RECRUITING	Fecal Microbiota Transplant and Re-introduction of Anti-PD-1 Therapy (Pembrolizumab or Nivolumab) for the Treatment of Metastatic Colorectal Cancer in Anti-PD-1 Non-responders
NCT04802876	PHASE2	ACTIVE_NOT_RECRUITING	Efficacy of Tislelizumab and Spartalizumab Across Multiple Cancer-types in Patients with PD1-high MRNA Expressing Tumors
NCT04963283	PHASE2	ACTIVE_NOT_RECRUITING	Study of Cabozantinib and Nivolumab in Refractory Metastatic Microsatellite Stable (MSS) Colorectal Cancer
NCT05312398	PHASE2	ACTIVE_NOT_RECRUITING	CAPRI 2 GOIM Study: Investigate the Efficacy and Safety of a Bio-marker Driven Cetuximab-based Treatment Regimen
NCT05504252	PHASE2	ACTIVE_NOT_RECRUITING	METIMMOX-2: Metastatic pMMR/MSS Colorectal Cancer - Shaping Anti-Tumor Immunity by Oxaliplatin
NCT05620134	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Study of JK08 in Patients with Unresectable Locally Advanced or Metastatic Cancer
NCT05627635	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	FOLFOX and Bevacizumab in Combination With Botensilimab and Balstilimab (3B-FOLFOX) for the Treatment of Microsatellite Stable (MSS) Metastatic Colorectal Cancer
NCT05672316	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Botensilimab, Balstilimab and Regorafenib for the Treatment of Patients With Microsatellite Stable Metastatic Colorectal Cancer Who Have Progressed on Prior Chemotherapy
NCT05731271	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A First-in-Human, Phase 1 Study of TST003 in Subjects With Solid Tumors
NCT05736731	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Safety and Efficacy of A2B530, a Logic-gated CAR T, in Participants With Solid Tumors That Express CEA and Have Lost HLA-A*02 Expression
NCT06051695	PHASE1/PHASE2	RECRUITING	A Study to Evaluate the Safety and Efficacy of Mesothelin-Targeting Logic-gated CAR T, in Participants With Solid Tumors That Express MSLN and Have Lost HLA-A*02 Expression
NCT06118658	PHASE2	NOT_YET_RECRUITING	Chemotherapy Sequential Tislelizumab After Radical Resection in Patients With dMMR/MSI-H or POLE/POLD1 Mutations
NCT06195670	PHASE1/PHASE2	NOT_YET_RECRUITING	Clinical Study of Short-course Radiotherapy Followed by Fruquintinib Plus Sintilimab vs Bevacizumab Plus Capecitabine as First Line Treatment in Advanced mCRC
NCT06640166	PHASE2	RECRUITING	Encorafenib + Cetuximab Beyond Progression in Combination With FOLFIRI in Patients With BRAF V600E Mutated Metastatic Colorectal Cancer Progressing on Encorafenib + Cetuximab.
NCT06682793	PHASE1/PHASE2	RECRUITING	A Study to Evaluate the Safety and Efficacy of A2B395, an Allogeneic Logic-gated CAR T, in Participants With Solid Tumors That Express EGFR and Have Lost HLA-A*02 Expression
NCT06753721	PHASE1/PHASE2	NOT_YET_RECRUITING	An Open-label, Multicenter, Single-arm Clinical Study on the Use of Doxorubicin Liposome in Combination With CapOX and Bevacizumab Regimen for First-line Treatment of Advanced Colorectal Adenocarcinoma With SMAD4R361H/C Mutation.
NCT06943820	PHASE1/PHASE2	RECRUITING	AK129 Combination Therapy for Advanced Solid Tumors
NCT07130903	PHASE2	RECRUITING	Amplitude-Modulated Radiofrequency Electromagnetic Fields (AM RF EMF) in Combination With Fruquintinib in Refractory Metastatic Colorectal Cancer
NCT07147231	PHASE1/PHASE2	RECRUITING	Testing the Effectiveness of the Anti-cancer Drug Pidnarulex (CX-5461), in Combination With Another Anti-cancer Drug Cemiplimab (REGN2810), in Treating Refractory Microsatellite Stable Colorectal Cancer
NCT07407465	PHASE2	RECRUITING	Upfront Trastuzumab-Deruxtecan Plus Capecitabine and Bevacizumab for Patients With HER-2 Positive Metastatic Colorectal Cancer.
NCT07551596	PHASE2	NOT_YET_RECRUITING	Testing the Combination of Anti-Cancer Drugs, Botensilimab (AGEN1181) and Balstilimab (AGEN2034), After Standard Treatment for Colorectal Cancer, Combat Trial
NCT07589517	PHASE1/PHASE2	RECRUITING	Dual-Targeting CAR-NK Cells in Biomarker-Selected Advanced Colorectal Cancer
NCT07595874	PHASE2	NOT_YET_RECRUITING	Neoadjuvant Botensilimab and Balstilimab for the Treatment of Advanced Resectable Colorectal Cancer NEST3
NCT00034190	PHASE2	COMPLETED	Safety and Efficacy of S-8184 in Second Line Treatment of Stage III or IV Colorectal Adenocarcinoma
NCT00165217	PHASE2	COMPLETED	Capecitabine and Thalidomide in Previously Treated Metastatic Colorectal Carcinoma
NCT00168155	PHASE2	COMPLETED	Study of 5-FU + Leucovorin + CPT-11 in Patients With Resectable Liver Metastases From Colorectal Adenocarcinoma
NCT00597506	PHASE2	COMPLETED	Expanded Cohort for Metastatic Colorectal Cancer (MCRC) Using Bevacizumab + Everolimus

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BEVACIZUMAB	4	22
TIPIRACIL	4	13
TRIFLURIDINE	4	9
ENCORAFENIB	4	3
IRINOTECAN	4	3
REGORAFENIB	4	2
TUCATINIB	4	2
ATEZOLIZUMAB	4	1
AVELUMAB	4	1
CERITINIB	4	1
FRUQUINTINIB	4	1
NEOMYCIN	4	1
PANITUMUMAB	4	1
QUINACRINE	4	1
RELATLIMAB	4	1
SULINDAC	4	1
TRAMETINIB	4	1
TREMELIMUMAB	4	1
BALSTILIMAB	3	6
BOTENSILIMAB	3	6
AVUTOMETINIB	3	1
BRIVANIB	3	1
FRAMYCETIN	3	1
GUADECITABINE	3	1
IVONESCIMAB	3	1
PENPULIMAB	3	1
RINTATOLIMOD	3	1
SPARTALIZUMAB	3	1
DKN-01	2	1
FOSIFLOXURIDINE NAFALBENAMIDE	2	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 18 predictive associations from 18 curated evidence items; also 3 prognostic.

Molecular subtype	Therapy	Effect	Level	CIViC
BRAF V600E	Trametinib + Panitumumab	Sensitivity/Response	CIViC B	EID6124
EGFR Overexpression AND NOT KRAS Mutation	Chemotherapy + Cetuximab	Sensitivity/Response	CIViC B	EID11062
KMT2D Loss-of-function	Immune Checkpoint Inhibitor	Sensitivity/Response	CIViC B	EID12583
KRAS G12 OR KRAS G13 OR KRAS Q61	Chemotherapy + Cetuximab	Sensitivity/Response	CIViC B	EID11055
KRAS G13D	Chemotherapy + Cetuximab	Sensitivity/Response	CIViC B	EID11054
KRAS Wildtype	Cetuximab	Sensitivity/Response	CIViC B	EID11057
NOT KRAS Mutation AND ( BRAF V600E OR BRAF D594G )	Chemotherapy + Cetuximab	Sensitivity/Response	CIViC B	EID11060
EGFR Overexpression AND KRAS Mutation	Cetuximab	Adverse Response	CIViC B	EID11059
ERBB2 L755S	Trastuzumab + Leucovorin + Fluorouracil	Sensitivity/Response	CIViC C	EID4955
JUN Overexpression	Irbesartan	Sensitivity/Response	CIViC C	EID1633
KDR R961W	Regorafenib Anhydrous	Sensitivity/Response	CIViC C	EID1191
LMNA::NTRK1 Fusion	Entrectinib	Sensitivity/Response	CIViC C	EID2960
LMNA::NTRK1 Fusion AND NTRK1 G595R AND NTRK1 G667C	Entrectinib	Resistance	CIViC C	EID2961
BRAF V600E	Cetuximab	Sensitivity/Response	CIViC D	EID12446
KMT2D Loss-of-function	WRN Inhibitor HRO761 + WRN Inhibitor RO7589831	Sensitivity/Response	CIViC D	EID12584
TP53 R158L	MDM2 Inhibitor AMGMDS3	Resistance	CIViC D	EID10065
ALK Fusion	Crizotinib	Sensitivity/Response	CIViC E	EID1334
ROS1 Fusion	Crizotinib	Sensitivity/Response	CIViC E	EID1301