Bile duct cancer

Summary

Bile duct cancer (MONDO:0003059) is a cancer with 8 cohort genes (4 GWAS associations across 4 studies; 7 CIViC-evidence somatic drivers; 10 ClinVar predisposition records) and 94 clinical trials. The dominant Reactome pathway is Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha) (3 cohort genes). Top therapeutic interventions include cisplatin, tivozanib, and cabozantinib.

At a glance

• Classification: Cancer
• Cohort genes: 8
• GWAS associations: 4
• ClinVar variants: 10
• Clinical trials: 94

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	bile duct cancer
Mondo ID	MONDO:0003059
DOID	DOID:4606
GARD	0023352
Anatomy (UBERON)	UBERON:0002394
Is cancer (heuristic)	yes

Also known as: bile duct cancer · bile duct tumor · bile duct tumour · cancer of bile duct · malignant bile duct neoplasm · malignant neoplasm of bile duct · malignant neoplasm of the extrahepatic bile duct

Data availability: 10 ClinVar variants · 4 GWAS associations (4 studies).

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › digestive system disorder › digestive system cancer › liver cancer › biliary tract cancer › bile duct cancer

Related subtypes (1): biliary cystadenocarcinoma

Subtypes (4): intrahepatic bile duct cancer, bile duct sarcoma, bile duct carcinoma, malignant tumor of extrahepatic bile duct

Genetics & variants

GWAS landscape

4 GWAS associations across 4 studies. Top hits map to 2 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs144048895	2e-09	LMCD1-AS1	?	2.62
chr22:43945024	1e-08		T	0.6
rs148887053	1e-08	YPEL1 - MAPK1	?	2.57
rs77450240	4e-08	TRAPPC9	?	3.37

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90432143	Jiang Y	2023	116,382	213,325	A cross-disorder study to identify causal relationships, shared genetic variants, and genes across 21 digestive disorders.
GCST90432144	Jiang Y	2023	116,382	213,325	A cross-disorder study to identify causal relationships, shared genetic variants, and genes across 21 digestive disorders.
GCST90128463	Johnson R	2022	247	5,709	Leveraging genomic diversity for discovery in an electronic health record linked biobank: the UCLA ATLAS Community Health Initiative.
GCST90128460	Johnson R	2022	197	3,090	Leveraging genomic diversity for discovery in an electronic health record linked biobank: the UCLA ATLAS Community Health Initiative.

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	1
Tier 4: intronic/intergenic	3

MAF distribution

Bucket	Variants
common (>=0.05)	1
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	3

Functional consequences

Consequence	Count
intron_variant	2
unknown	1
TF_binding_site_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs144048895	3	8481603	TA>T,TAA		intron_variant	LMCD1-AS1	2e-09	Tier 4: intronic/intergenic
chr22:43945024							1e-08	Tier 4: intronic/intergenic
rs148887053	22	21745132	C>T		TF_binding_site_variant	YPEL1 - MAPK1	1e-08	Tier 3: regulatory
rs77450240	8	139850611	C>T	0.05	intron_variant	TRAPPC9	4e-08	Tier 4: intronic/intergenic

ClinVar germline variants

10 retrieved; paginated sample, class counts are floors:

3 conflicting classifications of pathogenicity, 3 benign/likely benign, 2 benign, 1 likely benign, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1050552	NM_000251.3(MSH2):c.935T>C (p.Leu312Pro)	MSH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
186120	NM_024675.4(PALB2):c.495C>T (p.Gly165=)	PALB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
811142	NM_001009944.3(PKD1):c.3344C>T (p.Thr1115Met)	PKD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
931576	NM_001009944.3(PKD1):c.8009A>G (p.Gln2670Arg)	PKD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
142140	NM_000051.4(ATM):c.1176C>G (p.Gly392=)	ATM	Benign	reviewed by expert panel
41632	NM_000249.4(MLH1):c.1151T>A (p.Val384Asp)	MLH1	Benign	reviewed by expert panel
1048915	NM_001009944.3(PKD1):c.2173G>A (p.Ala725Thr)	PKD1	Likely benign	no assertion criteria provided
257017	NM_001009944.3(PKD1):c.8298C>T (p.Ser2766=)	PKD1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
239216	NM_002691.4(POLD1):c.1017G>T (p.Ser339=)	POLD1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
184220	NM_000455.5(STK11):c.678C>T (p.Asn226=)	STK11	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 25 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
STK11	LoF	ANSC,CEAD,CESC,CHOL,LUAD,NSCLC,WDTC	CIViC #5534
PALB2	LoF	OVT	CIViC #15013
MLH1			CIViC #3532
MSH2			CIViC #3628
ATM	LoF	BLCA,BRCA,CCRCC,CHOL,CLLSLL,COAD,COADREAD,ESCA,HCC,LUAD,LUSC,MEL,NSCLC,PAAD,PANCREAS,PANET,PCM,PLMESO,PRAD,PROSTATE,STAD,UCEC,UTUC,WDTC	CIViC #69
POLD1	LoF	BRCA,ESCA	CIViC #4384
PRKD1	Act	CHOL,COADREAD,PRAD

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STK11	Orphanet:2869	Peutz-Jeghers syndrome
PALB2	Orphanet:1333	Familial pancreatic carcinoma
PALB2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
PALB2	Orphanet:178	Chordoma
PALB2	Orphanet:227535	Hereditary breast cancer
PALB2	Orphanet:84	Fanconi anemia
MLH1	Orphanet:144	Lynch syndrome
MLH1	Orphanet:252202	Constitutional mismatch repair deficiency syndrome
MSH2	Orphanet:144	Lynch syndrome
MSH2	Orphanet:252202	Constitutional mismatch repair deficiency syndrome
ATM	Orphanet:100	Ataxia-telangiectasia
ATM	Orphanet:1331	Familial prostate cancer
ATM	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
ATM	Orphanet:227535	Hereditary breast cancer
ATM	Orphanet:370109	Ataxia-telangiectasia variant
ATM	Orphanet:440437	Familial colorectal cancer Type X
ATM	Orphanet:52416	Mantle cell lymphoma
ATM	Orphanet:67038	B-cell chronic lymphocytic leukemia
PKD1	Orphanet:730	Autosomal dominant polycystic kidney disease
PKD1	Orphanet:88924	Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis
POLD1	Orphanet:363649	Mandibular hypoplasia-deafness-progeroid features-lipodystrophy syndrome
POLD1	Orphanet:440437	Familial colorectal cancer Type X
POLD1	Orphanet:447877	Polymerase proofreading-related polyposis
PRKD1	Orphanet:276145	Malignant epithelial tumor of salivary glands
PRKD1	Orphanet:708019	Congenital heart defect-ectodermal dysplasia- brachydactyly-telangiectasia syndrome

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
STK11	HGNC:11389	ENSG00000118046	Q15831	Serine/threonine-protein kinase STK11	clinvar
PALB2	HGNC:26144	ENSG00000083093	Q86YC2	Partner and localizer of BRCA2	clinvar
MLH1	HGNC:7127	ENSG00000076242	P40692	DNA mismatch repair protein Mlh1	clinvar
MSH2	HGNC:7325	ENSG00000095002	P43246	DNA mismatch repair protein Msh2	clinvar
ATM	HGNC:795	ENSG00000149311	Q13315	Serine-protein kinase ATM	clinvar
PKD1	HGNC:9008	ENSG00000008710	P98161	Polycystin-1	clinvar
POLD1	HGNC:9175	ENSG00000062822	P28340	DNA polymerase delta catalytic subunit	clinvar
PRKD1	HGNC:9407	ENSG00000184304	Q15139	Serine/threonine-protein kinase D1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
STK11	Serine/threonine-protein kinase STK11	Tumor suppressor serine/threonine-protein kinase that controls the activity of AMP-activated protein kinase (AMPK) family members, thereby playing a role in various processes such as cell metabolism, cell polarity, apoptosis and DNA damage…
PALB2	Partner and localizer of BRCA2	Plays a critical role in homologous recombination repair (HRR) through its ability to recruit BRCA2 and RAD51 to DNA breaks.
MLH1	DNA mismatch repair protein Mlh1	Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR).
MSH2	DNA mismatch repair protein Msh2	Component of the post-replicative DNA mismatch repair system (MMR).
ATM	Serine-protein kinase ATM	Serine/threonine protein kinase which activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor.
PKD1	Polycystin-1	Component of a heteromeric calcium-permeable ion channel formed by PKD1 and PKD2 that is activated by interaction between PKD1 and a Wnt family member, such as WNT3A and WNT9B.
POLD1	DNA polymerase delta catalytic subunit	As the catalytic component of the trimeric (Pol-delta3 complex) and tetrameric DNA polymerase delta complexes (Pol-delta4 complex), plays a crucial role in high fidelity genome replication, including in lagging strand synthesis, and repair.
PRKD1	Serine/threonine-protein kinase D1	Serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of MAPK8/JNK1 and Ras signaling, Golgi membrane integrity and tr…

Protein-family classification

Druggable: 4 · Difficult: 2 · Unknown: 2 · Druggable fraction: 0.5

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	3	10.4×	0.011
Antibody/Immunoglobulin	1	3.6×	0.608
Scaffold/PPI	1	2.2×	0.632
Transcription factor	1	1.0×	0.805
Other/Unknown	2	0.5×	0.984

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STK11	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
PALB2	Scaffold/PPI	no		WD40/YVTN_repeat-like_dom_sf, PALB2_WD40, WD40_repeat_dom_sf
MLH1	Other/Unknown	no		MutL/Mlh/PMS, DNA_mismatch_S5_2-like, Ribsml_uS5_D2-typ_fold_subgr
MSH2	Other/Unknown	no		DNA_mismatch_repair_MutS_C, DNA_mismatch_repair_MutS-lik_N, DNA_mismatch_repair_MutS_core
ATM	Kinase	yes	2.7.11.1	PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
PKD1	Antibody/Immunoglobulin	yes		GPS, LRRNT, PC1
POLD1	Transcription factor	no	2.7.7.7	DNA-dir_DNA_pol_B_exonuc, DNA-dir_DNA_pol_B_multi_dom, DNA-dir_DNA_pol_B
PRKD1	Kinase	yes	2.7.11.13	Prot_kinase_dom, PH_domain, PKC_DAG/PE

Expression context

Cohort genes with no expression data: 0.

7 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
ventricular zone	3
oocyte	2
secondary oocyte	2
hindlimb stylopod muscle	1
left testis	1
right testis	1
buccal mucosa cell	1
deltoid	1
skeletal muscle tissue of rectus abdominis	1
tibialis anterior	1
calcaneal tendon	1
colonic epithelium	1
corpus callosum	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
mucosa of transverse colon	1
primordial germ cell in gonad	1
seminal vesicle	1
thoracic aorta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STK11	238	ubiquitous	marker	left testis, right testis, hindlimb stylopod muscle
PALB2	232	ubiquitous	yes	secondary oocyte, buccal mucosa cell, oocyte
MLH1	296	ubiquitous	marker	tibialis anterior, skeletal muscle tissue of rectus abdominis, deltoid
MSH2	278	ubiquitous	marker	secondary oocyte, oocyte, ventricular zone
ATM	286	ubiquitous	marker	calcaneal tendon, colonic epithelium, corpus callosum
PKD1	290		marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
POLD1	134	ubiquitous	marker	mucosa of transverse colon, ventricular zone, primordial germ cell in gonad
PRKD1	239	ubiquitous	marker	ventricular zone, seminal vesicle, thoracic aorta

Protein interactions among cohort

Intra-cohort edges: 8.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATM	7,383
PALB2	5,641
STK11	5,146
MSH2	4,537
MLH1	4,435
POLD1	4,000
PRKD1	2,131
PKD1	1,370

Intra-cohort edges

A	B	Sources
ATM	MLH1	string_interaction
ATM	MSH2	string_interaction
ATM	STK11	string_interaction
MLH1	MSH2	string_interaction
MLH1	POLD1	string_interaction
MSH2	POLD1	string_interaction
PALB2	STK11	string_interaction
PKD1	PRKD1	string_interaction

Structural data

PDB: 7 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MSH2	P43246	30
ATM	Q13315	14
PKD1	P98161	13
MLH1	P40692	7
POLD1	P28340	6
STK11	Q15831	4
PALB2	Q86YC2	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PRKD1	Q15139	68.99

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 99. 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
Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)	3	305.9×	4e-06	MLH1, MSH2, POLD1
Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)	3	305.9×	4e-06	MLH1, MSH2, POLD1
Diseases of DNA repair	3	214.1×	8e-06	MLH1, MSH2, ATM
Mismatch Repair	2	713.8×	5e-05	MLH1, MSH2
Diseases of Mismatch Repair (MMR)	2	713.8×	5e-05	MLH1, MSH2
Transcriptional Regulation by TP53	4	31.0×	7e-05	STK11, MLH1, MSH2, ATM
HDR through Homologous Recombination (HRR)	3	71.4×	1e-04	PALB2, ATM, POLD1
TP53 Regulates Transcription of DNA Repair Genes	3	68.0×	1e-04	MLH1, MSH2, ATM
DNA Repair	3	36.9×	6e-04	MLH1, MSH2, ATM
Impaired BRCA2 binding to PALB2	2	114.2×	0.001	PALB2, ATM
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	2	105.7×	0.001	PALB2, ATM
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	2	105.7×	0.001	PALB2, ATM
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	2	105.7×	0.001	PALB2, ATM
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	2	98.5×	0.001	PALB2, ATM
Homologous DNA Pairing and Strand Exchange	2	95.2×	0.001	PALB2, ATM
RNA Polymerase II Transcription	4	11.3×	0.001	STK11, MLH1, MSH2, ATM
Resolution of D-loop Structures through Holliday Junction Intermediates	2	75.1×	0.002	PALB2, ATM
Meiosis	2	71.4×	0.002	MLH1, ATM
Gene expression (Transcription)	4	8.9×	0.003	STK11, MLH1, MSH2, ATM
Reproduction	2	47.6×	0.004	MLH1, ATM
Generic Transcription Pathway	4	7.5×	0.005	STK11, MLH1, MSH2, ATM
Defective Mismatch Repair Associated With MLH1	1	713.8×	0.006	MLH1
Defective Mismatch Repair Associated With MSH3	1	713.8×	0.006	MSH2
Defective Mismatch Repair Associated With MSH6	1	713.8×	0.006	MSH2
Defective Mismatch Repair Associated With PMS2	1	713.8×	0.006	MLH1
Regulation of TP53 Activity	2	33.2×	0.006	STK11, ATM
Meiotic recombination	2	32.4×	0.006	MLH1, ATM
Regulation of TP53 Activity through Phosphorylation	2	29.4×	0.007	STK11, ATM
Defective Mismatch Repair Associated With MSH2	1	475.8×	0.007	MSH2
Sensing of DNA Double Strand Breaks	1	237.9×	0.014	ATM

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
positive regulation of isotype switching to IgA isotypes	2	702.2×	7e-04	MLH1, MSH2
meiotic telomere clustering	2	468.1×	8e-04	MLH1, ATM
positive regulation of isotype switching to IgG isotypes	2	383.0×	9e-04	MLH1, MSH2
protein autophosphorylation	3	54.5×	0.001	STK11, ATM, PRKD1
somatic hypermutation of immunoglobulin genes	2	263.3×	0.001	MLH1, MSH2
isotype switching	2	210.7×	0.001	MLH1, MSH2
mismatch repair	2	162.0×	0.002	MLH1, MSH2
determination of adult lifespan	2	108.0×	0.003	MSH2, ATM
double-strand break repair via nonhomologous end joining	2	105.3×	0.003	MLH1, ATM
response to ionizing radiation	2	102.8×	0.003	STK11, ATM
establishment of cell polarity	2	95.8×	0.003	STK11, PKD1
regulation of signal transduction by p53 class mediator	2	95.8×	0.003	STK11, ATM
somitogenesis	2	93.6×	0.003	PALB2, ATM
regulation of cell cycle	3	28.0×	0.003	STK11, ATM, PKD1
intrinsic apoptotic signaling pathway in response to DNA damage	2	81.0×	0.004	MLH1, ATM
negative regulation of TORC1 signaling	2	81.0×	0.004	STK11, ATM
somatic recombination of immunoglobulin genes involved in immune response	1	2106.5×	0.006	MSH2
meiotic metaphase I homologous chromosome alignment	1	2106.5×	0.006	MLH1
metanephric distal tubule morphogenesis	1	2106.5×	0.006	PKD1
positive regulation of vesicle transport along microtubule	1	2106.5×	0.006	STK11
positive regulation of autophagy	2	52.0×	0.007	STK11, PRKD1
double-strand break repair	2	50.8×	0.007	MSH2, ATM
regulation of skeletal muscle contraction by modulation of calcium ion sensitivity of myofibril	1	1053.2×	0.008	PRKD1
meiotic spindle midzone assembly	1	1053.2×	0.008	MLH1
nitrogen cycle metabolic process	1	1053.2×	0.008	PKD1
mesonephric tubule development	1	1053.2×	0.008	PKD1
establishment of RNA localization to telomere	1	1053.2×	0.008	ATM
establishment of protein-containing complex localization to telomere	1	1053.2×	0.008	ATM
positive regulation of telomerase catalytic core complex assembly	1	1053.2×	0.008	ATM
double-strand break repair via homologous recombination	2	39.0×	0.009	PALB2, ATM

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 3 · Undrugged: 5

Druggability breadth: 6 of 8 evidence-associated genes (75%) 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
STK11	FEDRATINIB
ATM	AMIODARONE HYDROCHLORIDE
PRKD1	INGENOL MEBUTATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATM	35	4
PRKD1	26	4
STK11	17	4
PALB2	0	0
MLH1	0	0
MSH2	0	0
PKD1	0	0
POLD1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	STK11
PACRITINIB	4	STK11
NINTEDANIB	4	PRKD1, STK11
SUNITINIB	4	PRKD1, STK11
MIDOSTAURIN	4	PRKD1, STK11
AMIODARONE HYDROCHLORIDE	4	ATM
FURAZOLIDONE	4	ATM
ESTRADIOL ACETATE	4	ATM
NAFTIFINE HYDROCHLORIDE	4	ATM
METHYSERGIDE MALEATE	4	ATM
AMITRIPTYLINE HYDROCHLORIDE	4	ATM
XYLOMETAZOLINE HYDROCHLORIDE	4	ATM
FLUVOXAMINE MALEATE	4	ATM
ESTRADIOL VALERATE	4	ATM
PERMETHRIN	4	ATM
MITOTANE	4	ATM
TICLOPIDINE HYDROCHLORIDE	4	ATM
ENOXIMONE	4	ATM
METHYLENE BLUE ANHYDROUS	4	ATM
DITHIAZANINE IODIDE	4	ATM
ETHACRYNIC ACID	4	ATM
SECNIDAZOLE	4	ATM
MENADIONE	4	ATM
FENOFIBRATE	4	ATM
DIPYRIDAMOLE	4	ATM
INGENOL MEBUTATE	4	PRKD1
TAMOXIFEN	4	PRKD1
NERATINIB	4	PRKD1
BRIGATINIB	4	PRKD1
CRIZOTINIB	4	PRKD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
PRKD1	660	Binding:650, Functional:10
STK11	244	Binding:244
ATM	240	Binding:233, Functional:5, ADMET:2
PKD1	27	Binding:27
MSH2	9	Binding:9
POLD1	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
STK11	2.7.11.1	non-specific serine/threonine protein kinase
ATM	2.7.11.1	non-specific serine/threonine protein kinase
POLD1	2.7.7.7	DNA-directed DNA polymerase
PRKD1	2.7.11.13	protein kinase C

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
STK11	244
ATM	240
PRKD1	660

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).

Drug repurposing candidates

30 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)
FEDRATINIB	4	STK11
PACRITINIB	4	STK11
NINTEDANIB	4	PRKD1, STK11
SUNITINIB	4	PRKD1, STK11
MIDOSTAURIN	4	PRKD1, STK11
AMIODARONE HYDROCHLORIDE	4	ATM
FURAZOLIDONE	4	ATM
ESTRADIOL ACETATE	4	ATM
NAFTIFINE HYDROCHLORIDE	4	ATM
METHYSERGIDE MALEATE	4	ATM
AMITRIPTYLINE HYDROCHLORIDE	4	ATM
XYLOMETAZOLINE HYDROCHLORIDE	4	ATM
FLUVOXAMINE MALEATE	4	ATM
ESTRADIOL VALERATE	4	ATM
PERMETHRIN	4	ATM
MITOTANE	4	ATM
TICLOPIDINE HYDROCHLORIDE	4	ATM
ENOXIMONE	4	ATM
METHYLENE BLUE ANHYDROUS	4	ATM
DITHIAZANINE IODIDE	4	ATM
ETHACRYNIC ACID	4	ATM
SECNIDAZOLE	4	ATM
MENADIONE	4	ATM
FENOFIBRATE	4	ATM
DIPYRIDAMOLE	4	ATM
INGENOL MEBUTATE	4	PRKD1
TAMOXIFEN	4	PRKD1
NERATINIB	4	PRKD1
BRIGATINIB	4	PRKD1
CRIZOTINIB	4	PRKD1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	STK11, ATM, PRKD1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PKD1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	PALB2, MLH1, MSH2, POLD1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PKD1	27	PRKD1
PALB2	0	—
MLH1	0	—
MSH2	9	—
POLD1	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 94.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	44
PHASE2	21
PHASE1	13
PHASE4	6
PHASE1/PHASE2	4
PHASE3	3
PHASE2/PHASE3	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00280709	PHASE4	COMPLETED	Biliary Metal Stent Study: Metal Stents for Management of Distal Malignant Biliary Obstruction
NCT01041612	PHASE4	COMPLETED	Comparing Covered Self-expandable Metallic Stent (SEMS) Above/Across the Sphincter of Oddi
NCT01111591	PHASE4	UNKNOWN	Cyclooxygenase-2 Inhibitor for Adjuvant Anticancer Effect in Patients With Biliary-pancreas Cancer
NCT01256034	PHASE4	COMPLETED	Effects of Preoperative Immunonutrition in Patients Undergoing Pancreaticoduodenectomy
NCT01256047	PHASE4	COMPLETED	Effects of Preoperative Immunonutrition in Patients Undergoing Hepatectomy
NCT01969110	PHASE4	UNKNOWN	Additional Effects of Perioperative Immunonutrition in Patients Undergoing Pancreaticoduodenectomy
NCT07155525	PHASE3	RECRUITING	Tissue Adhesive Glue Modified Cyanoacrylate (Glubran® 2) in Soft Pancreas
NCT00809081	PHASE3	UNKNOWN	Early Enteral Feeding After Pylorus Preserving Pancreatoduodenectomy
NCT01755013	PHASE2/PHASE3	UNKNOWN	Photodynamic Therapy (PDT) for Palliation of Cholangiocarcinoma
NCT02591030	PHASE2/PHASE3	COMPLETED	Safety and Efficacy of Modified Folfirinox Versus Gemcis in Bile Duct Tumours
NCT02853474	PHASE3	COMPLETED	Early Palliative Care in Patients With Metastatic Upper Gastrointestinal Cancers Treated With First-line Chemotherapy
NCT03086993	PHASE2/PHASE3	UNKNOWN	Percutaneous Hepatic Perfusion vs. Cisplatin/Gemcitabine in Patients With Intrahepatic Cholangiocarcinoma
NCT02628067	PHASE2	ACTIVE_NOT_RECRUITING	Study of Pembrolizumab (MK-3475) in Participants With Advanced Solid Tumors (MK-3475-158/KEYNOTE-158)
NCT05286814	PHASE2	RECRUITING	PDS01ADC in Combination With Hepatic Artery Infusion Pump (HAIP) and Systemic Therapy for Subjects With Metastatic Colorectal Cancer, Intrahepatic Cholangiocarcinoma, or Metastatic Adrenocortical Carcinoma
NCT05655949	PHASE2	RECRUITING	Y-90 With Durvalumab/Gem/Cis in Intrahepatic Cholangio
NCT05849480	PHASE1/PHASE2	RECRUITING	A Study of CDX-1140, a CD40 Agonist, in Combination With Capecitabine and Oxaliplatin (CAPOX) and Keytruda in Subjects With Biliary Tract Carcinoma (BTC)
NCT06048133	PHASE2	RECRUITING	Study of Gemcitabine, Cisplatin, AB680 and AB122 During First Line Treatment of Advanced Biliary Tract Cancers (QUIC)
NCT06274879	PHASE2	RECRUITING	Safety of Biliary Intraductal Radiofrequency Ablation in Patients With Unresectable Extrahepatic Biliary Tract Cancer
NCT06730581	PHASE2	NOT_YET_RECRUITING	Utidelone Capsule Monotherapy for Patients with Advanced Solid Tumors
NCT07030140	PHASE2	RECRUITING	Phase II Study of Neoadjuvant Tislelizumab Plus Radiotherapy and GP Chemotherapy for Borderline/Unresectable Hilar Cholangiocarcinoma
NCT00356161	PHASE2	UNKNOWN	HAI Via Interventionally Implanted Port Catheter Systems
NCT00832637	PHASE2	TERMINATED	Gemcitabine, Oxaliplatin, Tarceva &/or Cisplatin in HCC & Biliary Tree Cancers
NCT01151761	PHASE2	TERMINATED	Phase II SBRT & Chemo for Unresectable Cholangiocarcinoma Followed by Liver Transplantation
NCT01317069	PHASE2	UNKNOWN	A Randomized, Open, Prospective Clinical Research of Fluorouracil Implant to Improve Surgical Gallbladder Cancer and Bile Duct Cancer
NCT01954745	PHASE2	COMPLETED	Cabozantinib (XL-184) Monotherapy for Advanced Cholangiocarcinoma
NCT02821754	PHASE2	COMPLETED	A Pilot Study of Combined Immune Checkpoint Inhibition in Combination With Ablative Therapies in Subjects With Hepatocellular Carcinoma (HCC) or Biliary Tract Carcinomas (BTC)
NCT03058289	PHASE1/PHASE2	COMPLETED	A Phase 1/2 Safety Study of Intratumorally Dosed INT230-6
NCT03111732	PHASE2	COMPLETED	Pembrolizumab, a Monoclonal Antibody Against PD-1, in Combination With Capecitabine and Oxaliplatin (CAPOX) in People With Advanced Biliary Tract Carcinoma (BTC)
NCT03602079	PHASE1/PHASE2	COMPLETED	Study of A166 in Patients With Relapsed/Refractory Cancers Expressing HER2 Antigen or Having Amplified HER2 Gene
NCT04076761	PHASE2	TERMINATED	Study of TRIFLURIDINE/TIPIRACIL in Previously Treated Cholangiocarcinoma
NCT04298008	PHASE2	UNKNOWN	AZD6738 Plus Durvalumab in Biliary Tract Cancer
NCT04298021	PHASE2	UNKNOWN	DDR-Umbrella Study of DDR Targeting Agents in Advanced Biliary Tract Cancer
NCT04383210	PHASE2	TERMINATED	Study of Seribantumab in Adult Patients With NRG1 Gene Fusion Positive Advanced Solid Tumors
NCT04566133	PHASE2	TERMINATED	Combination of Trametinib (MEK Inhibitor) and Hydroxychloroquine (HCQ) (Autophagy Inhibitor) in Patients With KRAS Mutation Refractory Bile Tract Carcinoma (BTC).
NCT05000294	PHASE1/PHASE2	SUSPENDED	Atezolizumab Plus Tivozanib in Immunologically Cold Tumor Types
NCT05712356	PHASE2	TERMINATED	A Study of LSTA1 When Added to Standard of Care Versus Standard of Care Alone in Patients With Advanced Solid Tumors
NCT05911425	PHASE2	UNKNOWN	Combined Treatment of Treated Bile Duct Cancer
NCT05277766	PHASE1	RECRUITING	Intraperitoneal Aerosolized Nanoliposomal Irinotecan (Nal-IRI) in Peritoneal Carcinomatosis From Gastrointestinal Cancer
NCT05858736	PHASE1	ACTIVE_NOT_RECRUITING	Safety, PK and Efficacy of AI-061 in Advanced Solid Tumors
NCT06043466	PHASE1	RECRUITING	A Clinical Trial Targeting CEA Chimeric Antigen Receptor T (CAR-T) for CEA Positive Advanced Malignant Solid Tumors

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CISPLATIN	4	7
TIVOZANIB	4	2
CABOZANTINIB	4	1
FLOXURIDINE	4	1
MELPHALAN	4	1
TIPIRACIL	4	1
TREMELIMUMAB	4	1
TRIFLURIDINE	4	1
CERALASERTIB	3	2
SASANLIMAB	3	1
ZIMBERELIMAB	3	1
CDX-1140	2	1
CERTEPETIDE	2	1
DKN-01	2	1
QUEMLICLUSTAT	2	1
SERIBANTUMAB	2	1
TRASTUZUMAB BOTIDOTIN	2	1
YTTRIUM Y-90	2	1
CHEMBL3648328	0	2
CHEMBL4215501	0	1
CHEMBL4849721	0	1
CHEMBL5433950	0	1
EXELIXIS	0	1