Pancreatic ductal adenocarcinoma

Summary

Pancreatic ductal adenocarcinoma (MONDO:0005184) is a disease (an umbrella term covering 5 Mondo subtypes) with 11 cohort genes and 419 clinical trials. The dominant Reactome pathway is SHC1 events in ERBB2 signaling (3 cohort genes). Molecularly, KRAS G12D confers sensitivity to Setidegrasib in Pancreatic Ductal Adenocarcinoma (CIViC Level B); 14 further subtype–drug associations are mapped below. Top therapeutic interventions include capecitabine, pemetrexed, and irinotecan.

At a glance

• Umbrella term: 5 Mondo subtypes
• Cohort genes: 11
• Clinical trials: 419
• Precision-medicine evidence (CIViC): 15 subtype–drug associations

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pancreatic ductal adenocarcinoma
Mondo ID	MONDO:0005184
EFO	EFO:0002517
MeSH	D021441
DOID	DOID:3498, DOID:3587
ICD-11	581089833
NCIT	C9120
UMLS	C1335302
MedGen	277490
GARD	0027716
Anatomy (UBERON)	UBERON:0007329
Is cancer (heuristic)	no

Also known as: ductal adenocarcinoma of pancreas · ductal adenocarcinoma of the pancreas · pancreas ductal adenocarcinoma · pancreas tubular adenocarcinoma · pancreatic duct adenocarcinoma · pancreatic ductal adenocarcinoma · pancreatic ductal carcinoma · pancreatic tubular adenocarcinoma

Data availability: 276 cell lines.

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 › tubular adenocarcinoma › pancreatic ductal adenocarcinoma

Related subtypes (3): invasive tubular breast carcinoma, gastric tubular adenocarcinoma, well-differentiated fetal adenocarcinoma of the lung

Subtypes (5): pancreatic signet ring cell adenocarcinoma, pancreatic foamy gland adenocarcinoma, mixed ductal-endocrine carcinoma of pancreas, colloid carcinoma of the pancreas, undifferentiated pancreatic carcinoma

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: 36 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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
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
ERBB3	Orphanet:137776	Lethal congenital contracture syndrome type 2
ERBB3	Orphanet:388	Hirschsprung disease
HSPB1	Orphanet:139525	Distal hereditary motor neuropathy type 2
HSPB1	Orphanet:99940	Autosomal dominant Charcot-Marie-Tooth disease type 2F
IDH1	Orphanet:163634	Maffucci syndrome
IDH1	Orphanet:251576	Gliosarcoma
IDH1	Orphanet:251579	Giant cell glioblastoma
IDH1	Orphanet:296	Ollier disease
IDH1	Orphanet:86845	Acute myeloid leukaemia with myelodysplasia-related features
IDH1	Orphanet:99646	Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria
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
SMAD4	Orphanet:1333	Familial pancreatic carcinoma
SMAD4	Orphanet:2588	Myhre syndrome
SMAD4	Orphanet:329971	Generalized juvenile polyposis/juvenile polyposis coli
SMAD4	Orphanet:774	Hereditary hemorrhagic telangiectasia
SMAD4	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection

Cohort genes → proteins

11 cohort genes, 11 distinct canonical proteins.

Evidence partition

Subset	Genes
civic_only	11

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
STK11	HGNC:11389	ENSG00000118046	Q15831	Serine/threonine-protein kinase STK11	civic_evidence
SIRT1	HGNC:14929	ENSG00000096717	Q96EB6	NAD-dependent protein deacetylase sirtuin-1	civic_evidence
PALB2	HGNC:26144	ENSG00000083093	Q86YC2	Partner and localizer of BRCA2	civic_evidence
NQO1	HGNC:2874	ENSG00000181019	P15559	NAD(P)H dehydrogenase [quinone] 1	civic_evidence
CIP2A	HGNC:29302	ENSG00000163507	Q8TCG1	Protein CIP2A	civic_evidence
ERBB2	HGNC:3430	ENSG00000141736	P04626	Receptor tyrosine-protein kinase erbB-2	civic_evidence
ERBB3	HGNC:3431	ENSG00000065361	P21860	Receptor tyrosine-protein kinase erbB-3	civic_evidence
HSPB1	HGNC:5246	ENSG00000106211	P04792	Heat shock protein beta-1	civic_evidence
IDH1	HGNC:5382	ENSG00000138413	O75874	Isocitrate dehydrogenase [NADP] cytoplasmic	civic_evidence
KRAS	HGNC:6407	ENSG00000133703	P01116	GTPase KRas	civic_evidence
SMAD4	HGNC:6770	ENSG00000141646	Q13485	SMAD family member 4	civic_evidence

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…
SIRT1	NAD-dependent protein deacetylase sirtuin-1	NAD-dependent protein deacetylase that links transcriptional regulation directly to intracellular energetics and participates in the coordination of several separated cellular functions such as cell cycle, response to DNA damage, metabolis…
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.
NQO1	NAD(P)H dehydrogenase [quinone] 1	Flavin-containing quinone reductase that catalyzes two-electron reduction of quinones to hydroquinones using either NADH or NADPH as electron donors.
CIP2A	Protein CIP2A	Acts as an inhibitor of protein phosphatase PP2A.
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.
ERBB3	Receptor tyrosine-protein kinase erbB-3	Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins.
HSPB1	Heat shock protein beta-1	Small heat shock protein which functions as a molecular chaperone probably maintaining denatured proteins in a folding-competent state.
IDH1	Isocitrate dehydrogenase [NADP] cytoplasmic	Catalyzes the NADP(+)-dependent oxidative decarboxylation of isocitrate (D-threo-isocitrate) to 2-ketoglutarate (2-oxoglutarate), which is required by other enzymes such as the phytanoyl-CoA dioxygenase.
KRAS	GTPase KRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
SMAD4	SMAD family member 4	In muscle physiology, plays a central role in the balance between atrophy and hypertrophy.

Protein-family classification

Druggable: 7 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.64

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	7.6×	0.020
Enzyme (other)	4	4.4×	0.020
Scaffold/PPI	1	1.6×	0.641
Other/Unknown	3	0.5×	0.987

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
SIRT1	Enzyme (other)	yes	2.3.1.286	Sirtuin, Ssirtuin_cat_dom, Sirtuin_cat_small_dom_sf
PALB2	Scaffold/PPI	no		WD40/YVTN_repeat-like_dom_sf, PALB2_WD40, WD40_repeat_dom_sf
NQO1	Enzyme (other)	yes	1.6.5.2	Flavodoxin_fold, Flavoprotein-like_sf, NAD(P)H_dehydrogenase_qn
CIP2A	Other/Unknown	no		ARM-like, ARM-type_fold, CIP2A
ERBB2	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
ERBB3	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
HSPB1	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, HSP20-like_chaperone
IDH1	Enzyme (other)	yes	1.1.1.42	Isocitrate_DH_NADP, IsoCit/isopropylmalate_DH_CS, IsoPropMal-DH-like_dom
KRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
SMAD4	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf

Expression context

Cohort genes with no expression data: 0.

10 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)	11
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	3
calcaneal tendon	2
ganglionic eminence	2
secondary oocyte	2
lower esophagus mucosa	2
jejunal mucosa	2
trigeminal ganglion	2
hindlimb stylopod muscle	1
left testis	1
right testis	1
buccal mucosa cell	1
oocyte	1
endometrium epithelium	1
gall bladder	1
stromal cell of endometrium	1
primordial germ cell in gonad	1
right uterine tube	1
sural nerve	1
dorsal root ganglion	1
ascending 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
SIRT1	280	ubiquitous	marker	calcaneal tendon, ganglionic eminence, ventricular zone
PALB2	232	ubiquitous	yes	secondary oocyte, buccal mucosa cell, oocyte
NQO1	285	ubiquitous	marker	endometrium epithelium, gall bladder, stromal cell of endometrium
CIP2A	175	ubiquitous	marker	ventricular zone, secondary oocyte, primordial germ cell in gonad
ERBB2	276	ubiquitous	marker	lower esophagus mucosa, right uterine tube, sural nerve
ERBB3	274	broad	marker	trigeminal ganglion, jejunal mucosa, dorsal root ganglion
HSPB1	299	ubiquitous	marker	lower esophagus mucosa, ascending aorta, thoracic aorta
IDH1	294	ubiquitous	marker	corpus epididymis, jejunal mucosa, adrenal tissue
KRAS	298	ubiquitous	marker	trigeminal ganglion, pylorus, nipple
SMAD4	288	ubiquitous	marker	ventricular zone, ganglionic eminence, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRAS	14,509
ERBB2	9,659
SIRT1	8,285
SMAD4	7,320
PALB2	5,641
HSPB1	5,491
IDH1	5,464
STK11	5,146
ERBB3	4,511
NQO1	2,566

Intra-cohort edges

A	B	Sources
ERBB2	ERBB3	biogrid_interaction, intact, string_interaction
ERBB2	KRAS	string_interaction
KRAS	STK11	string_interaction
PALB2	STK11	string_interaction
SIRT1	STK11	biogrid_interaction
SMAD4	STK11	string_interaction

Structural data

PDB: 11 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRAS	P01116	511
ERBB2	P04626	63
IDH1	O75874	61
NQO1	P15559	28
ERBB3	P21860	23
SMAD4	Q13485	12
SIRT1	Q96EB6	9
HSPB1	P04792	6
STK11	Q15831	4
PALB2	Q86YC2	4
CIP2A	Q8TCG1	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 201. Enrichment computed across 11 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
SHC1 events in ERBB2 signaling	3	142.8×	9e-05	ERBB2, ERBB3, KRAS
Signaling by ERBB2 TMD/JMD mutants	3	142.8×	9e-05	ERBB2, ERBB3, KRAS
Signaling by ERBB2 KD Mutants	3	126.9×	9e-05	ERBB2, ERBB3, KRAS
FOXO-mediated transcription	3	100.8×	1e-04	STK11, SIRT1, SMAD4
GRB7 events in ERBB2 signaling	2	380.7×	4e-04	ERBB2, ERBB3
Constitutive Signaling by Overexpressed ERBB2	2	190.3×	0.002	ERBB2, KRAS
Downregulation of ERBB2:ERBB3 signaling	2	163.1×	0.002	ERBB2, ERBB3
ERBB2 Activates PTK6 Signaling	2	163.1×	0.002	ERBB2, ERBB3
ERBB2 Regulates Cell Motility	2	142.8×	0.002	ERBB2, ERBB3
PI3K events in ERBB2 signaling	2	134.3×	0.002	ERBB2, ERBB3
Signaling by ERBB2 ECD mutants	2	134.3×	0.002	ERBB2, KRAS
GRB2 events in ERBB2 signaling	2	126.9×	0.002	ERBB2, KRAS
Downregulation of ERBB2 signaling	2	76.1×	0.005	ERBB2, ERBB3
Signaling by ERBB2	2	69.2×	0.005	ERBB2, ERBB3
RAF/MAP kinase cascade	3	18.3×	0.006	ERBB2, ERBB3, KRAS
Abnormal conversion of 2-oxoglutarate to 2-hydroxyglutarate	1	1142.0×	0.011	IDH1
NADPH regeneration	1	571.0×	0.019	IDH1
Loss of Function of SMAD4 in Cancer	1	380.7×	0.019	SMAD4
SMAD4 MH2 Domain Mutants in Cancer	1	380.7×	0.019	SMAD4
SMAD2/3 MH2 Domain Mutants in Cancer	1	380.7×	0.019	SMAD4
Signaling by RAS GAP mutants	1	380.7×	0.019	KRAS
Signaling by RAS GTPase mutants	1	380.7×	0.019	KRAS
NFE2L2 regulating TCA cycle genes	1	380.7×	0.019	IDH1
Regulation of MITF-M dependent genes involved in metabolism	1	380.7×	0.019	SIRT1
PLCG1 events in ERBB2 signaling	1	285.5×	0.019	ERBB2
Drug-mediated inhibition of ERBB2 signaling	1	285.5×	0.019	ERBB2
Resistance of ERBB2 KD mutants to trastuzumab	1	285.5×	0.019	ERBB2
Resistance of ERBB2 KD mutants to sapitinib	1	285.5×	0.019	ERBB2
Resistance of ERBB2 KD mutants to tesevatinib	1	285.5×	0.019	ERBB2
Resistance of ERBB2 KD mutants to neratinib	1	285.5×	0.019	ERBB2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 11 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 apoptotic process	5	15.8×	0.003	SIRT1, PALB2, ERBB2, ERBB3, HSPB1
ERBB2-ERBB3 signaling pathway	2	306.4×	0.003	ERBB2, ERBB3
positive regulation of cellular senescence	2	235.7×	0.004	SIRT1, KRAS
Schwann cell development	2	191.5×	0.004	ERBB2, ERBB3
negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway	2	170.2×	0.004	SIRT1, HSPB1
response to oxidative stress	3	35.6×	0.004	SIRT1, NQO1, IDH1
negative regulation of neuron apoptotic process	3	30.2×	0.006	SIRT1, ERBB3, KRAS
positive regulation of transforming growth factor beta receptor signaling pathway	2	95.8×	0.008	STK11, SMAD4
obsolete positive regulation of cell proliferation involved in heart valve morphogenesis	1	1532.0×	0.011	SMAD4
regulation of endodeoxyribonuclease activity	1	1532.0×	0.011	SIRT1
response to mineralocorticoid	1	1532.0×	0.011	KRAS
maintenance of nucleus location	1	1532.0×	0.011	SIRT1
regulation of phospholipid catabolic process	1	1532.0×	0.011	IDH1
female gonad morphogenesis	1	1532.0×	0.011	SMAD4
negative regulation of protein kinase C signaling	1	1532.0×	0.011	HSPB1
positive regulation of vesicle transport along microtubule	1	1532.0×	0.011	STK11
negative regulation of attachment of mitotic spindle microtubules to kinetochore	1	1532.0×	0.011	SIRT1
negative regulation of cardiac myofibril assembly	1	1532.0×	0.011	SMAD4
negative regulation of cellular response to testosterone stimulus	1	1532.0×	0.011	SIRT1
positive regulation of blood vessel endothelial cell migration	2	71.3×	0.011	SIRT1, HSPB1
negative regulation of protein catabolic process	2	66.6×	0.011	NQO1, SMAD4
glyoxylate cycle	1	766.0×	0.012	IDH1
negative regulation of prostaglandin biosynthetic process	1	766.0×	0.012	SIRT1
regulation of smooth muscle cell apoptotic process	1	766.0×	0.012	SIRT1
regulation of peroxisome proliferator activated receptor signaling pathway	1	766.0×	0.012	SIRT1
positive regulation of cardiac muscle tissue development	1	766.0×	0.012	ERBB3
regulation of phospholipid biosynthetic process	1	766.0×	0.012	IDH1
nephrogenic mesenchyme morphogenesis	1	766.0×	0.012	SMAD4
protein depropionylation	1	766.0×	0.012	SIRT1
broken chromosome clustering	1	766.0×	0.012	CIP2A

Therapeutics

Drugs indicated for this disease

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

Drug	Development status
Axitinib	Phase 3 (in late-stage trials)
Capecitabine	Phase 3 (in late-stage trials)
Erfonrilimab	Phase 3 (in late-stage trials)
Fluorouracil	Phase 3 (in late-stage trials)
Gemcitabine	Phase 3 (in late-stage trials)
Irinotecan	Phase 3 (in late-stage trials)
Momelotinib	Phase 3 (in late-stage trials)
Napabucasin	Phase 3 (in late-stage trials)
Oxaliplatin	Phase 3 (in late-stage trials)
Paclitaxel	Phase 3 (in late-stage trials)
Relacorilant	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Abemaciclib, Aldoxorubicin, Atezolizumab, Balstilimab, Bortezomib, CPI 613, Chlorambucil, Cisplatin, Defactinib, Dostarlimab, Durvalumab, Enfortumab Vedotin, Epacadostat, Gimeracil, Ivospemin, Niraparib, Nivolumab, Olaparib, Oleclumab, Oteracil, Paricalcitol, Pembrolizumab, Rucaparib, Sitagliptin, Sulfur Hexafluoride, Tegafur, Trabedersen, Tremelimumab, Vismodegib, Zimberelimab.

Drug target analysis

Approved (phase 4): 7 · Phase ≥3: 7 · Phased (≥1): 8 · Undrugged: 3

Druggability breadth: 10 of 11 evidence-associated genes (91%) 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
SIRT1	NIACINAMIDE
NQO1	DICUMAROL
ERBB2	CLOTRIMAZOLE
ERBB3	MOBOCERTINIB
IDH1	ENASIDENIB
KRAS	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ERBB2	83	4
ERBB3	23	4
STK11	17	4
KRAS	11	4
IDH1	10	4
SIRT1	6	4
NQO1	4	4
HSPB1	1	2
PALB2	0	0
CIP2A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	STK11
PACRITINIB	4	STK11
NINTEDANIB	4	STK11
SUNITINIB	4	STK11
MIDOSTAURIN	4	STK11
NIACINAMIDE	4	SIRT1
DICUMAROL	4	NQO1
CLOTRIMAZOLE	4	ERBB2
ERLOTINIB HYDROCHLORIDE	4	ERBB2
PONATINIB	4	ERBB2
AFATINIB	4	ERBB2, ERBB3
LAPATINIB DITOSYLATE	4	ERBB2
SORAFENIB	4	ERBB2
NERATINIB	4	ERBB2, ERBB3
IBRUTINIB	4	ERBB2
AFATINIB DIMALEATE	4	ERBB2
CABOZANTINIB	4	ERBB2
DACOMITINIB	4	ERBB2
DACOMITINIB ANHYDROUS	4	ERBB2
VANDETANIB	4	ERBB2, ERBB3
TRIBROMSALAN	4	ERBB2
BOSUTINIB	4	ERBB2, ERBB3
BITHIONOL	4	ERBB2
ASTEMIZOLE	4	ERBB2
EBASTINE	4	ERBB2
OSIMERTINIB	4	ERBB2, ERBB3
BRIGATINIB	4	ERBB2
ACALABRUTINIB	4	ERBB2
ZANUBRUTINIB	4	ERBB2
TUCATINIB	4	ERBB2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

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

Symbol	Assays	Type breakdown
ERBB2	1,221	Binding:1136, Functional:79, ADMET:6
KRAS	861	Binding:829, Functional:32
SIRT1	645	Binding:642, ADMET:3
IDH1	488	Binding:475, Functional:12, ADMET:1
NQO1	279	Binding:227, ADMET:48, Functional:4
STK11	244	Binding:244
ERBB3	169	Binding:169
HSPB1	70	Binding:70
CIP2A	17	Binding:17
SMAD4	6	Binding:6

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
STK11	2.7.11.1	non-specific serine/threonine protein kinase
SIRT1	2.3.1.286	protein acetyllysine N-acetyltransferase
NQO1	1.6.5.2	NAD(P)H dehydrogenase (quinone)
ERBB2	2.7.10.1	receptor protein-tyrosine kinase
ERBB3	2.7.10.1	receptor protein-tyrosine kinase
IDH1	1.1.1.42	isocitrate dehydrogenase (NADP+)
KRAS	3.6.5.2	small monomeric GTPase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
STK11	244
SIRT1	645
NQO1	279
ERBB2	1,221
ERBB3	169
IDH1	488
KRAS	861

Pharmacogenomics

Cohort genes with a PharmGKB record: 11; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

26 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)
FEDRATINIB	4	STK11
PACRITINIB	4	STK11
NINTEDANIB	4	STK11
SUNITINIB	4	STK11
MIDOSTAURIN	4	STK11
NIACINAMIDE	4	SIRT1
DICUMAROL	4	NQO1
CLOTRIMAZOLE	4	ERBB2
AFATINIB	4	ERBB2, ERBB3
LAPATINIB DITOSYLATE	4	ERBB2
SORAFENIB	4	ERBB2
IBRUTINIB	4	ERBB2
AFATINIB DIMALEATE	4	ERBB2
CABOZANTINIB	4	ERBB2
DACOMITINIB	4	ERBB2
DACOMITINIB ANHYDROUS	4	ERBB2
VANDETANIB	4	ERBB2, ERBB3
TRIBROMSALAN	4	ERBB2
BOSUTINIB	4	ERBB2, ERBB3
BITHIONOL	4	ERBB2
ASTEMIZOLE	4	ERBB2
EBASTINE	4	ERBB2
OSIMERTINIB	4	ERBB2, ERBB3
ACALABRUTINIB	4	ERBB2
ZANUBRUTINIB	4	ERBB2
TUCATINIB	4	ERBB2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	7	STK11, SIRT1, NQO1, ERBB2, ERBB3, IDH1, KRAS
B	Phased (≥1) drug, not yet approved	1	HSPB1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	PALB2, CIP2A, SMAD4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PALB2	0	—
CIP2A	17	—
SMAD4	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 419.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	124
PHASE2	95
PHASE1	89
PHASE1/PHASE2	66
PHASE3	18
EARLY_PHASE1	13
PHASE2/PHASE3	9
PHASE4	5

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05634720	PHASE4	ACTIVE_NOT_RECRUITING	Hepatic Artery Chemotherapy for Patients With Localized Pancreas Cancer
NCT02570529	PHASE4	WITHDRAWN	Prevention of Upper Gastrointestinal Hemorrhage Using Albis® in the Patients of Locally Advanced Pancreatic Cancer Who Underwent Concurrent Chemoradiotherapy
NCT04480268	PHASE4	UNKNOWN	PAXG Out in the Country
NCT06077487	PHASE4	TERMINATED	Ketamine-assisted Therapy for Advanced GI Cancer
NCT06199752	PHASE4	COMPLETED	Synergistic Immunomodulatory Effect of Synbiotics Pre and Postoperative Resection of Pancreatic Ductal Adenocarcinoma
NCT04793932	PHASE3	ACTIVE_NOT_RECRUITING	Short-course Versus Long-course Pre-operative Chemotherapy With mFOLFIRINOX or PAXG (CASSANDRA TRIAL)
NCT04927780	PHASE3	ACTIVE_NOT_RECRUITING	Perioperative or Adjuvant mFOLFIRINOX for Resectable Pancreatic Cancer
NCT04969731	PHASE3	RECRUITING	Safety and Efficacy of Immuncell-LC With Gemcitabine in Resectable Pancreatic Cancer
NCT05254171	PHASE2/PHASE3	RECRUITING	Study of Nab-Paclitaxel and Gemcitabine With or Without SBP-101 in Pancreatic Cancer
NCT05314998	PHASE3	NOT_YET_RECRUITING	Adjuvant Trial in Patients With Resected PDAC Randomized to Allocation of Oxaliplatin- or Gemcitabine-based Chemotherapy by Standard Clinical Criteria or by a Transcriptomic Treatment Specific Stratification Signature
NCT06079346	PHASE2/PHASE3	RECRUITING	A Study of OT-101 With mFOLFIRINOX in Patients With Advanced and Unresectable or Metastatic Pancreatic Cancer
NCT06115499	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	The PLATINUM Trial: Optimizing Chemotherapy for the Second-Line Treatment of Metastatic BRCA1/2 or PALB2-Associated Metastatic Pancreatic Cancer
NCT06608927	PHASE3	ACTIVE_NOT_RECRUITING	Study of Quemliclustat and Chemotherapy Versus Placebo and Chemotherapy in Patients With Metastatic Pancreatic Ductal Adenocarcinoma
NCT06782412	PHASE2/PHASE3	RECRUITING	Multicenter Validation Trial of [18F]AlF-FAPI-74 for PET Imaging of Cancer-associated Fibroblasts Through Fibroblast Activation Protein Inhibitors (FAPI) in Different Tumor Types
NCT06989437	PHASE2/PHASE3	RECRUITING	A Study to Learn About the Medicine Ponsegromab in Adults With Cancer of the Pancreas Which Has Spread and Caused Significant Body Weight Loss and Fatigue
NCT07076121	PHASE2/PHASE3	RECRUITING	A Study Comparing BMS-986504 in Combination With Nab-paclitaxel and Gemcitabine Versus Placebo in Combination With Nab-paclitaxel and Gemcitabine in Participants With Untreated Metastatic Pancreatic Ductal Adenocarcinoma With Homozygous MTAP Deletion (MountainTAP-30)
NCT07155525	PHASE3	RECRUITING	Tissue Adhesive Glue Modified Cyanoacrylate (Glubran® 2) in Soft Pancreas
NCT07165951	PHASE3	RECRUITING	Clinical Trial Comparing TQB2868 Injection Combined With Anlotinib Hydrochloride Capsules With Placebo Combined With Chemotherapy as First-line Treatment for Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC)
NCT07217717	PHASE3	RECRUITING	Using 18F-FAPI PET to Detect Metastatic Disease in Patients That Have Pancreatic Ductal Adenocarcinoma (PDAC)
NCT07219238	PHASE2/PHASE3	RECRUITING	Study to Evaluate the Diagnostic Performance of GEH300079 (68Ga) Injection PET/CT for Detection of PC in Patients With Colorectal, Gastric, Ovarian, or Pancreatic Cancers (PERISCOPE)
NCT07445295	PHASE3	NOT_YET_RECRUITING	Chiauranib Plus PD-1 Inhibitor, Albumin-paclitaxel and Gemcitabine in Patients With Metastatic Pancreatic Ductal Adenocarcinoma
NCT07490301	PHASE2/PHASE3	NOT_YET_RECRUITING	A Study to Assess Intravenous (IV) Telisotuzumab Adizutecan in Combination With Fluorouracil, Folinic Acid, and Oxaliplatin (FOLFOX) Compared to Standard of Care in Adult Participants With First-Line Metastatic Pancreatic Ductal Adenocarcinoma
NCT07491445	PHASE3	RECRUITING	Study of Daraxonrasib and Daraxonrasib + GnP as First-line Treatment in Patients With Metastatic Pancreatic Adenocarcinoma
NCT07562152	PHASE3	RECRUITING	Atebimetinib + GnP as a First Line Treatment in Patients With Metastatic Pancreatic Adenocarcinoma
NCT01013649	PHASE3	COMPLETED	Gemcitabine Hydrochloride With or Without Erlotinib Hydrochloride Followed by the Same Chemotherapy Regimen With or Without Radiation Therapy and Capecitabine or Fluorouracil in Treating Patients With Pancreatic Cancer That Has Been Removed by Surgery
NCT02101021	PHASE3	TERMINATED	Gemcitabine and Nab-paclitaxel Combined With Momelotinib in Participants With Previously Untreated Metastatic Pancreatic Ductal Adenocarcinoma
NCT02715804	PHASE3	TERMINATED	A Study of PEGylated Recombinant Human Hyaluronidase in Combination With Nab-Paclitaxel Plus Gemcitabine Compared With Placebo Plus Nab-Paclitaxel and Gemcitabine in Participants With Hyaluronan-High Stage IV Previously Untreated Pancreatic Ductal Adenocarcinoma
NCT03317886	PHASE3	UNKNOWN	Mesenteric Approach vs. Conventional Approach for Pancreatic Cancer
NCT04329949	PHASE3	TERMINATED	Study of Relacorilant in Combination With Nab-Paclitaxel in Patients With Metastatic Pancreatic Ductal Adenocarcinoma
NCT04935359	PHASE3	COMPLETED	Study of Efficacy and Safety of NIS793 in Combination With Standard of Care (SOC) Chemotherapy in First-line Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC) - daNIS-2
NCT05149326	PHASE3	UNKNOWN	KN046 in Subjects With Advanced Pancreatic Ductal Adenocarcinoma.
NCT05955157	PHASE2/PHASE3	UNKNOWN	Combined S-1 With DC+CIK As Maintenance Therapy For Advanced Pancreatic Ductal Adenocarcinoma
NCT02498613	PHASE2	ACTIVE_NOT_RECRUITING	A Phase 2 Study of Cediranib in Combination With Olaparib in Advanced Solid Tumors
NCT03608631	PHASE1/PHASE2	RECRUITING	iExosomes in Treating Participants With Metastatic Pancreas Cancer With KrasG12D Mutation
NCT03806309	PHASE2	ACTIVE_NOT_RECRUITING	OSE2101+FOLFIRI, or FOLFIRI Maintenance After FOLFIRINOX-based Induction Therapy in Advanced or Metastatic PDAC
NCT03977233	PHASE2	RECRUITING	Tumor Subtypes in Subjects on FOLFIRINOX With Non-Metastatic Pancreatic Cancer
NCT04083599	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	GEN1042 Safety Trial and Anti-tumor Activity in Participants With Malignant Solid Tumors
NCT04111172	PHASE2	ACTIVE_NOT_RECRUITING	A Vaccine (Ad5.F35-hGCC-PADRE) for the Treatment of Gastrointestinal Adenocarcinoma
NCT04146298	PHASE1/PHASE2	RECRUITING	Mutant KRAS G12V-specific TCR Transduced T Cell Therapy for Advanced Pancreatic Cancer
NCT04657068	PHASE1/PHASE2	RECRUITING	A Study of ART0380 for the Treatment of Advanced or Metastatic Solid Tumors

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CAPECITABINE	4	9
PEMETREXED	4	6
IRINOTECAN	4	3
NIRAPARIB	4	3
COBIMETINIB	4	2
DOSTARLIMAB	4	2
OLAPARIB	4	2
PARICALCITOL	4	2
TREMELIMUMAB	4	2
VISMODEGIB	4	2
ABEMACICLIB	4	1
BRIGATINIB	4	1
CERITINIB	4	1
CHLORAMBUCIL	4	1
DARATUMUMAB	4	1
ENCORAFENIB	4	1
ENFORTUMAB VEDOTIN	4	1
ERLOTINIB HYDROCHLORIDE	4	1
GEMCITABINE HYDROCHLORIDE	4	1
GLIPIZIDE	4	1
LENVATINIB MESYLATE	4	1
MOMELOTINIB	4	1
NERATINIB	4	1
PANCRELIPASE	4	1
PEGCETACOPLAN	4	1
PONATINIB	4	1
ROMIDEPSIN	4	1
RUCAPARIB	4	1
SELUMETINIB	4	1
TORIPALIMAB	4	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 15 predictive associations from 15 curated evidence items; also 19 oncogenic, 5 prognostic.

Molecular subtype	Therapy	Effect	Level	CIViC
KRAS G12D	Setidegrasib	Sensitivity/Response	CIViC B	EID12938
APP::NRG1 Fusion	Afatinib	Sensitivity/Response	CIViC C	EID7493
ATP1B1::NRG1 Fusion	Afatinib	Sensitivity/Response	CIViC C	EID7492
IDH1 R132H	Ivosidenib	Sensitivity/Response	CIViC C	EID5987
PALB2 Mutation	Talazoparib	Sensitivity/Response	CIViC C	EID10835
CIP2A Underexpression	Gemcitabine	Sensitivity/Response	CIViC D	EID1118
ERBB2 V777L	Neratinib	Sensitivity/Response	CIViC D	EID11569
ERBB2 V777L AND KRAS G12C	ARS-1620 + Neratinib	Sensitivity/Response	CIViC D	EID11572
ERBB2 V842I	Neratinib	Sensitivity/Response	CIViC D	EID11570
ERBB3 EXPRESSION	9F7-F11 + Pertuzumab	Sensitivity/Response	CIViC D	EID865
HSPB1 EXPRESSION	Gemcitabine	Sensitivity/Response	CIViC D	EID939
KRAS G12C AND ERBB2 V842I	ARS-1620 + Neratinib	Sensitivity/Response	CIViC D	EID11573
NQO1 Overexpression	NSC84167	Sensitivity/Response	CIViC D	EID12560
STK11 Loss	Roflumilast	Sensitivity/Response	CIViC D	EID12555
NR4A2 Overexpression	Gemcitabine + C-DIM 12	Resistance	CIViC D	EID12649