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Atlas / Disease / Her2-receptor negative breast cancer

Her2-receptor negative breast cancer

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Summary

Her2-receptor negative breast cancer (MONDO:0000618) is a cancer with 6 cohort genes (4 GWAS associations across 8 studies; 6 CIViC-evidence somatic drivers). Molecularly, BRCA1 Loss-of-function confers sensitivity to Olaparib in Her2-receptor Negative Breast Cancer (CIViC Level A); 27 further subtype–drug associations are mapped below.

At a glance

  • Classification: Cancer
  • Cohort genes: 6
  • GWAS associations: 4
  • Precision-medicine evidence (CIViC): 28 subtype–drug associations

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

FieldValue
Canonical nameHer2-receptor negative breast cancer
Mondo IDMONDO:0000618
EFOEFO:0009780
DOIDDOID:0060080
NCITC168519
SNOMED CT431396003
UMLSC4733095
MedGen1684659
Is cancer (heuristic)yes

Data availability: 4 GWAS associations (8 studies).

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › cancer › carcinoma › breast carcinoma › breast carcinoma by gene expression profile › Her2-receptor negative breast cancer

Related subtypes (7): progesterone-receptor positive breast cancer, progesterone-receptor negative breast cancer, breast tumor luminal A or B, HER2 positive breast carcinoma, normal breast-like subtype of breast carcinoma, estrogen-receptor positive breast cancer, estrogen-receptor negative breast cancer

Subtypes (2): triple-negative breast carcinoma, hormone receptor-positive breast cancer

Genetics & variants

GWAS landscape

4 GWAS associations across 8 studies. Top hits map to 3 distinct genes (as reported by GWAS).

Top associations by p-value

rsIDp-valueGeneRisk alleleOdds ratio
rs132584342e-09NACA4P - LINC02845G0.03
rs621920523e-09DNER?0.15
rs80303941e-08THSD4?2.47
rs12431842e-08MLLT10T0.03

Top studies (by case count)

StudyLead authorYearCasesControlsTitle
GCST90446472Sun X202416,4990Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants that Confer Risk for Breast Cancer.
GCST90454347Zhang H202013,80091,477Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.
GCST007418Lacson JCA20179321,310Genome-Wide Testing of Exonic Variants and Breast Cancer Risk in the California Teachers Study.
GCST90029047Morra A202100Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment.
GCST90029048Morra A202100Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment.
GCST90029049Morra A202100Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment.
GCST90029060Morra A202100Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment.
GCST90029061Morra A202100Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

TierVariants
Tier 1: coding0
Tier 2: splice/UTR0
Tier 3: regulatory0
Tier 4: intronic/intergenic4

MAF distribution

BucketVariants
common (>=0.05)3
low_freq (0.01-0.05)0
rare (<0.01)0
unknown1

Functional consequences

ConsequenceCount
intron_variant3
intergenic_variant1

Top variants

rsIDChrPosAllelesMAFConsequenceGenep-valueTier
rs132584348101379857G>A,T0.05intergenic_variantNACA4P - LINC028452e-09Tier 4: intronic/intergenic
rs621920522229507632C>Tintron_variantDNER3e-09Tier 4: intronic/intergenic
rs80303941571344902C>A,G,T0.05intron_variantTHSD41e-08Tier 4: intronic/intergenic
rs12431841021643008T>C0.05intron_variantMLLT102e-08Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 51 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

GeneintOGen roleCancer typesCIViC
BRCA1LoFBLCA,BRCA,MEL,OVTCIViC #6
BRCA2LoFBLCA,BRCA,CESC,CHOL,HCC,HNSC,LUSC,MBL,OVT,PAAD,PRAD,PROSTATE,RCC,VULVACIViC #7
CDKN2ALoFACYC,BLCA,BRCA,CHOL,COAD,COADREAD,CSCC,EGC,ESCA,ESCC,GBM,HCC,HNSC,LGGNOS,LUAD,LUSC,MEL,MLYM,NPC,NSCLC,OS,PAAD,PANCREAS,RCC,SKCM,SKIN,STAD,STOMACH,WDTCCIViC #14
ERBB2ActBLCA,BRCA,CESC,CHOL,COADREAD,EGC,ESCA,ESCC,LMS,LUAD,NSCLC,OVT,PRCC,READ,STAD,UCECCIViC #20
AKT1ActALL,BRCA,CESC,COADREAD,PRAD,PROSTATE,SARCNOS,UCEC,WDTCCIViC #2
PIK3CAActACYC,ANGS,ANSC,BCC,BLADDER,BLCA,BRCA,CCRCC,CEAD,CESC,CHOL,COAD,COADREAD,EPM,ESCA,ESCC,GB,GBM,HCC,HGGNOS,HNSC,LGGNOS,LIPO,LMS,LUAD,LUSC,MBL,MGCT,NPC,NSCLC,OVT,PAAD,PAST,PLMESO,PRAD,PRCC,PROSTATE,RCC,SACA,SKCM,SOFT_TISSUE,STAD,UCEC,UCS,UTUC,VULVA,WDTCCIViC #37

Orphanet rare-disease linkage (cohort genes)

GeneOrphanet IDRare disease
BRCA1Orphanet:1331Familial prostate cancer
BRCA1Orphanet:1333Familial pancreatic carcinoma
BRCA1Orphanet:145Hereditary breast and/or ovarian cancer syndrome
BRCA1Orphanet:168829Primary peritoneal carcinoma
BRCA1Orphanet:227535Hereditary breast cancer
BRCA1Orphanet:667662Breast implant-associated anaplastic large cell lymphoma
BRCA1Orphanet:694963Inflammatory breast cancer
BRCA1Orphanet:70567Cholangiocarcinoma
BRCA1Orphanet:84Fanconi anemia
BRCA2Orphanet:1331Familial prostate cancer
BRCA2Orphanet:1333Familial pancreatic carcinoma
BRCA2Orphanet:145Hereditary breast and/or ovarian cancer syndrome
BRCA2Orphanet:178Chordoma
BRCA2Orphanet:227535Hereditary breast cancer
BRCA2Orphanet:319462Inherited cancer-predisposing syndrome due to biallelic BRCA2 mutations
BRCA2Orphanet:440437Familial colorectal cancer Type X
BRCA2Orphanet:654Nephroblastoma
BRCA2Orphanet:667662Breast implant-associated anaplastic large cell lymphoma
BRCA2Orphanet:694963Inflammatory breast cancer
BRCA2Orphanet:70567Cholangiocarcinoma
BRCA2Orphanet:84Fanconi anemia
CDKN2AOrphanet:1333Familial pancreatic carcinoma
CDKN2AOrphanet:1501Adrenocortical carcinoma
CDKN2AOrphanet:252206Melanoma and neural system tumor syndrome
CDKN2AOrphanet:404560Familial atypical multiple mole melanoma syndrome
CDKN2AOrphanet:524Li-Fraumeni syndrome
CDKN2AOrphanet:585909B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
CDKN2AOrphanet:618Familial melanoma
CDKN2AOrphanet:99861Precursor T-cell acute lymphoblastic leukemia
ERBB2Orphanet:213726Serous carcinoma of the corpus uteri
ERBB2Orphanet:2800Extramammary Paget disease
ERBB2Orphanet:388Hirschsprung disease
ERBB2Orphanet:99976Adenocarcinoma of the oesophagus and oesophagogastric junction
AKT1Orphanet:201Cowden syndrome
AKT1Orphanet:2495Meningioma
AKT1Orphanet:744Proteus syndrome
PIK3CAOrphanet:140944CLOVES syndrome
PIK3CAOrphanet:144Lynch syndrome
PIK3CAOrphanet:168984CLAPO syndrome
PIK3CAOrphanet:201Cowden syndrome
PIK3CAOrphanet:210159Adult hepatocellular carcinoma
PIK3CAOrphanet:221061Familial cerebral cavernous malformation
PIK3CAOrphanet:2495Meningioma
PIK3CAOrphanet:276280Hemihyperplasia-multiple lipomatosis syndrome
PIK3CAOrphanet:295239Macrodactyly of fingers, unilateral
PIK3CAOrphanet:295243Macrodactyly of toes, unilateral
PIK3CAOrphanet:314662Segmental progressive overgrowth syndrome with fibroadipose hyperplasia
PIK3CAOrphanet:60040Megalencephaly-capillary malformation-polymicrogyria syndrome
PIK3CAOrphanet:714737Diffuse capillary malformation with overgrowth
PIK3CAOrphanet:90308Capillary-lymphatic-venous malformation with segmental distribution

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

SubsetGenes
civic_only6

Cohort genes (full)

SymbolHGNCEnsemblUniProtNameEvidence
BRCA1HGNC:1100ENSG00000012048P38398Breast cancer type 1 susceptibility proteincivic_evidence
BRCA2HGNC:1101ENSG00000139618P51587Breast cancer type 2 susceptibility proteincivic_evidence
CDKN2AHGNC:1787ENSG00000147889P42771Cyclin-dependent kinase inhibitor 2Acivic_evidence
ERBB2HGNC:3430ENSG00000141736P04626Receptor tyrosine-protein kinase erbB-2civic_evidence
AKT1HGNC:391ENSG00000142208P31749RAC-alpha serine/threonine-protein kinasecivic_evidence
PIK3CAHGNC:8975ENSG00000121879P42336Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoformcivic_evidence

Cohort function summary

Lead sentence per gene, UniProt-curated.

SymbolProtein nameFunction (lead sentence)
BRCA1Breast cancer type 1 susceptibility proteinE3 ubiquitin-protein ligase that specifically mediates the formation of ‘Lys-6’-linked polyubiquitin chains and plays a central role in DNA repair by facilitating cellular responses to DNA damage.
BRCA2Breast cancer type 2 susceptibility proteinInvolved in double-strand break repair and/or homologous recombination.
CDKN2ACyclin-dependent kinase inhibitor 2AActs as a negative regulator of the proliferation of normal cells by interacting strongly with CDK4 and CDK6.
ERBB2Receptor tyrosine-protein kinase erbB-2Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding.
AKT1RAC-alpha serine/threonine-protein kinaseAKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis.
PIK3CAPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoformPhosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides.

Protein-family classification

Druggable: 3 · Difficult: 2 · Unknown: 1 · 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.

FamilyGenesFoldFDR
Kinase313.9×0.003
Scaffold/PPI12.9×0.601
Transcription factor11.4×0.719
Other/Unknown10.3×0.993

Per-gene assignment

SymbolFamilyDruggable?ECInterPro (top 3)
BRCA1Transcription factorno2.3.2.27BRCT_dom, Znf_RING, BRCA1
BRCA2Other/UnknownnoBRCA2_repeat, NA-bd_OB-fold, BRCA2_OB_1
CDKN2AScaffold/PPInoAnkyrin_rpt-contain_sf, Ank_Repeat/CDKN_Inhibitor, Tumor_suppres_ARF
ERBB2Kinaseyes2.7.10.1Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
AKT1Kinaseyes2.7.11.1Prot_kinase_dom, AGC-kinase_C, PH_domain
PIK3CAKinaseyes2.7.1.137PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom, PI3K_accessory_dom

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

BucketGenes
narrow (1-5 tissues)0
moderate (6-20)0
broad (>20)6
unknown0

Top tissues across cohort

TissueCohort genes
male germ line stem cell (sensu Vertebrata) in testis2
ventricular zone2
primordial germ cell in gonad1
secondary oocyte1
cervix squamous epithelium1
parotid gland1
pituitary gland1
lower esophagus mucosa1
right uterine tube1
sural nerve1
endometrium epithelium1
ganglionic eminence1
stromal cell of endometrium1
adrenal tissue1
calcaneal tendon1
tendon1

Per-gene tissue summary (top 30)

SymbolBgee breadthFANTOM5 breadthSCXATop tissues
BRCA1208ubiquitousmarkerventricular zone, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
BRCA2184ubiquitousmarkermale germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, ventricular zone
CDKN2A220ubiquitousmarkerparotid gland, cervix squamous epithelium, pituitary gland
ERBB2276ubiquitousmarkerlower esophagus mucosa, right uterine tube, sural nerve
AKT1273ubiquitousmarkerstromal cell of endometrium, ganglionic eminence, endometrium epithelium
PIK3CA284ubiquitousmarkercalcaneal tendon, adrenal tissue, tendon

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

SymbolInteractor count
AKT116,601
ERBB29,659
CDKN2A9,311
BRCA19,064
PIK3CA5,157
BRCA24,839

Intra-cohort edges

ABSources
AKT1PIK3CAbiogrid_interaction, string_interaction
BRCA1BRCA2string_interaction
ERBB2PIK3CAstring_interaction

Structural data

PDB: 6 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

SymbolUniProtPDB entries
PIK3CAP42336135
ERBB2P0462663
AKT1P3174943
BRCA1P3839833
BRCA2P5158714
CDKN2AP427715

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 270. Enrichment computed across 6 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

PathwayCohort genesFoldFDRSample cohort genes
Defective homologous recombination repair (HRR) due to PALB2 loss of function2317.2×6e-04BRCA1, BRCA2
Downregulation of ERBB2:ERBB3 signaling2271.9×6e-04ERBB2, AKT1
Diseases of DNA Double-Strand Break Repair2271.9×6e-04BRCA1, BRCA2
Defective homologous recombination repair (HRR) due to BRCA2 loss of function2271.9×6e-04BRCA1, BRCA2
Cellular response to chemical stress371.4×6e-04BRCA1, CDKN2A, AKT1
Regulation of TP53 Activity366.4×6e-04BRCA1, CDKN2A, AKT1
KEAP1-NFE2L2 pathway360.1×6e-04BRCA1, CDKN2A, AKT1
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling348.4×6e-04ERBB2, AKT1, PIK3CA
Cell Cycle424.0×6e-04BRCA1, BRCA2, CDKN2A, AKT1
PI3K events in ERBB2 signaling2223.9×8e-04ERBB2, PIK3CA
Signaling by ERBB2 ECD mutants2223.9×8e-04ERBB2, PIK3CA
Resolution of D-Loop Structures2211.5×8e-04BRCA1, BRCA2
Diseases of DNA repair2190.3×9e-04BRCA1, BRCA2
Regulation of TP53 Expression and Degradation2173.0×0.001CDKN2A, AKT1
Impaired BRCA2 binding to PALB22152.3×0.001BRCA1, BRCA2
Signaling by ERBB2 KD Mutants2141.0×0.001ERBB2, PIK3CA
Defective homologous recombination repair (HRR) due to BRCA1 loss of function2141.0×0.001BRCA1, BRCA2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function2141.0×0.001BRCA1, BRCA2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function2141.0×0.001BRCA1, BRCA2
PIP3 activates AKT signaling333.4×0.001ERBB2, AKT1, PIK3CA
Transcriptional Regulation by TP53331.0×0.001BRCA1, CDKN2A, AKT1
CD28 dependent PI3K/Akt signaling2131.3×0.001AKT1, PIK3CA
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)2131.3×0.001BRCA1, BRCA2
Homologous DNA Pairing and Strand Exchange2126.9×0.001BRCA1, BRCA2
Downregulation of ERBB2 signaling2126.9×0.001ERBB2, AKT1
Signaling by ERBB22115.3×0.001ERBB2, AKT1
FLT3 Signaling2115.3×0.001AKT1, PIK3CA
Homology Directed Repair2102.9×0.001BRCA1, BRCA2
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)2102.9×0.001BRCA1, BRCA2
Impaired BRCA2 binding to RAD512102.9×0.001BRCA1, BRCA2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO termCohort genesFoldFDRSample cohort genes
negative regulation of mammary gland epithelial cell proliferation21123.5×2e-04BRCA2, CDKN2A
negative regulation of immature T cell proliferation in thymus2936.2×2e-04CDKN2A, ERBB2
epidermal growth factor receptor signaling pathway3123.9×2e-04ERBB2, AKT1, PIK3CA
phosphatidylinositol 3-kinase/protein kinase B signal transduction3105.3×2e-04ERBB2, AKT1, PIK3CA
anoikis2432.1×5e-04AKT1, PIK3CA
negative regulation of macroautophagy2374.5×5e-04AKT1, PIK3CA
regulation of DNA damage checkpoint2374.5×5e-04BRCA1, BRCA2
insulin-like growth factor receptor signaling pathway2165.2×0.002AKT1, PIK3CA
cellular response to ionizing radiation2137.0×0.003BRCA1, BRCA2
positive regulation of protein localization to nucleus2130.6×0.003CDKN2A, AKT1
positive regulation of smooth muscle cell proliferation2110.1×0.004AKT1, PIK3CA
cellular response to epidermal growth factor stimulus2106.0×0.004ERBB2, AKT1
cellular senescence298.5×0.004BRCA2, CDKN2A
glucose metabolic process285.1×0.005AKT1, PIK3CA
response to muscle inactivity12808.7×0.005PIK3CA
mammalian oogenesis stage12808.7×0.005AKT1
positive regulation of endodeoxyribonuclease activity12808.7×0.005AKT1
regulation of tRNA methylation12808.7×0.005AKT1
negative regulation of protein maturation12808.7×0.005AKT1
response to butyrate12808.7×0.005PIK3CA
insulin receptor signaling pathway273.9×0.005AKT1, PIK3CA
double-strand break repair267.7×0.005BRCA1, BRCA2
positive regulation of cell growth261.1×0.006ERBB2, AKT1
cellular response to insulin stimulus256.7×0.006AKT1, PIK3CA
cellular response to tumor necrosis factor254.5×0.007BRCA1, AKT1
double-strand break repair via homologous recombination252.0×0.007BRCA1, BRCA2
nuclear body organization11404.3×0.007CDKN2A
negative regulation of protein localization to lysosome11404.3×0.007AKT1
mitotic recombination-dependent replication fork processing11404.3×0.007BRCA2
negative regulation of cell growth248.0×0.007BRCA1, CDKN2A

Therapeutics

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 4 · Phased (≥1): 4 · Undrugged: 2

Druggability breadth: 5 of 6 evidence-associated genes (83%) 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.

SymbolExample approved molecule
BRCA1RIBOFLAVIN
ERBB2CLOTRIMAZOLE
AKT1CAPIVASERTIB
PIK3CAIDELALISIB

Top cohort targets by molecule count

SymbolMoleculesMax phase
ERBB2834
PIK3CA674
AKT1304
BRCA1124
BRCA200
CDKN2A00

Drugs targeting cohort genes (top 30)

MoleculeMax phaseTargets in cohort
RIBOFLAVIN4BRCA1
DAUNORUBICIN HYDROCHLORIDE4BRCA1
TOPOTECAN HYDROCHLORIDE4BRCA1
DAUNORUBICIN4BRCA1
DOXORUBICIN HYDROCHLORIDE4BRCA1
MESALAMINE4BRCA1
DIPYRIDAMOLE4BRCA1
CLOTRIMAZOLE4ERBB2
ERLOTINIB HYDROCHLORIDE4ERBB2
PONATINIB4ERBB2
AFATINIB4ERBB2
LAPATINIB DITOSYLATE4ERBB2
SORAFENIB4ERBB2
NERATINIB4ERBB2
IBRUTINIB4ERBB2
AFATINIB DIMALEATE4ERBB2
CABOZANTINIB4ERBB2
DACOMITINIB4ERBB2
DACOMITINIB ANHYDROUS4ERBB2
VANDETANIB4ERBB2
TRIBROMSALAN4ERBB2
BOSUTINIB4ERBB2
BITHIONOL4ERBB2
ASTEMIZOLE4ERBB2
EBASTINE4ERBB2
OSIMERTINIB4ERBB2
BRIGATINIB4ERBB2
ACALABRUTINIB4ERBB2
ZANUBRUTINIB4ERBB2
TUCATINIB4ERBB2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

SymbolAssaysType breakdown
PIK3CA2,034Binding:2009, ADMET:19, Toxicity:4, Functional:2
AKT11,942Binding:1900, Functional:34, ADMET:7, Toxicity:1
ERBB21,221Binding:1136, Functional:79, ADMET:6
BRCA113Binding:9, Functional:4
CDKN2A2Binding:2

Cohort enzymes (BRENDA EC)

SymbolEC numbersNames
BRCA12.3.2.27RING-type E3 ubiquitin transferase
ERBB22.7.10.1receptor protein-tyrosine kinase
AKT12.7.11.1non-specific serine/threonine protein kinase
PIK3CA2.7.1.137, 2.7.1.153, 2.7.11.1phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase

Cohort genes with high screening signal

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

SymbolChEMBL assays
ERBB21,221
AKT11,942
PIK3CA2,034

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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.

CompoundMax phaseCohort target (bioactivity)
RIBOFLAVIN4BRCA1
DAUNORUBICIN HYDROCHLORIDE4BRCA1
TOPOTECAN HYDROCHLORIDE4BRCA1
DAUNORUBICIN4BRCA1
DOXORUBICIN HYDROCHLORIDE4BRCA1
MESALAMINE4BRCA1
DIPYRIDAMOLE4BRCA1
CLOTRIMAZOLE4ERBB2
ERLOTINIB HYDROCHLORIDE4ERBB2
PONATINIB4ERBB2
AFATINIB4ERBB2
LAPATINIB DITOSYLATE4ERBB2
SORAFENIB4ERBB2
NERATINIB4ERBB2
IBRUTINIB4ERBB2
AFATINIB DIMALEATE4ERBB2
CABOZANTINIB4ERBB2
DACOMITINIB4ERBB2
DACOMITINIB ANHYDROUS4ERBB2
VANDETANIB4ERBB2
TRIBROMSALAN4ERBB2
BOSUTINIB4ERBB2
BITHIONOL4ERBB2
ASTEMIZOLE4ERBB2
EBASTINE4ERBB2
OSIMERTINIB4ERBB2
BRIGATINIB4ERBB2
ACALABRUTINIB4ERBB2
ZANUBRUTINIB4ERBB2
TUCATINIB4ERBB2

Druggability pyramid

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

TierDefinitionGenesSymbols
AApproved (phase 4 drug)4BRCA1, ERBB2, AKT1, PIK3CA
BPhased (≥1) drug, not yet approved0
CDruggable family + PDB, no drug0
DDruggable family + AlphaFold only, no drug0
EDifficult family or no structure, no drug2BRCA2, CDKN2A

Undrugged target profiles

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

SymbolChEMBL assaysDrugged partners (top 3)
BRCA20BRCA1
CDKN2A2—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 28 predictive associations from 30 curated evidence items; also 1 prognostic.

Molecular subtypeTherapyEffectLevelCIViC
BRCA1 Loss-of-functionOlaparibSensitivity/ResponseCIViC AEID11201 +1
BRCA2 Loss-of-functionOlaparibSensitivity/ResponseCIViC AEID11202 +1
AKT1 E17KCapivasertib + FulvestrantSensitivity/ResponseCIViC AEID12181
PIK3CA C420RCapivasertib + FulvestrantSensitivity/ResponseCIViC AEID12183
PIK3CA E542KFulvestrant + CapivasertibSensitivity/ResponseCIViC AEID12184
PIK3CA E545AFulvestrant + CapivasertibSensitivity/ResponseCIViC AEID12185
PIK3CA E545DCapivasertib + FulvestrantSensitivity/ResponseCIViC AEID12186
PIK3CA E545GFulvestrant + CapivasertibSensitivity/ResponseCIViC AEID12189
PIK3CA E545KFulvestrant + CapivasertibSensitivity/ResponseCIViC AEID12188
PIK3CA E545QFulvestrant + CapivasertibSensitivity/ResponseCIViC AEID12187
PIK3CA G1049RCapivasertib + FulvestrantSensitivity/ResponseCIViC AEID12198
PIK3CA H1047LCapivasertib + FulvestrantSensitivity/ResponseCIViC AEID12197
PIK3CA H1047RFulvestrant + CapivasertibSensitivity/ResponseCIViC AEID12196
PIK3CA H1047YCapivasertib + FulvestrantSensitivity/ResponseCIViC AEID12195
PIK3CA M1043ICapivasertib + FulvestrantSensitivity/ResponseCIViC AEID12194
PIK3CA M1043VFulvestrant + CapivasertibSensitivity/ResponseCIViC AEID12193
PIK3CA N345KCapivasertib + FulvestrantSensitivity/ResponseCIViC AEID12182
PIK3CA Q546EFulvestrant + CapivasertibSensitivity/ResponseCIViC AEID12190
PIK3CA Q546KCapivasertib + FulvestrantSensitivity/ResponseCIViC AEID12191
PIK3CA Q546PCapivasertib + FulvestrantSensitivity/ResponseCIViC AEID12192
PIK3CA R88QCapivasertib + FulvestrantSensitivity/ResponseCIViC AEID12034
BRCA1 MutationOlaparibSensitivity/ResponseCIViC BEID5830
BRCA2 MutationOlaparibSensitivity/ResponseCIViC BEID11425
COX2 OverexpressionCelecoxibSensitivity/ResponseCIViC BEID10155
ERBB2 NON-AMPLIFICATIONLapatinibSensitivity/ResponseCIViC BEID3052
PALB2 Oncogenic Mutations (loss of function alterations)TalazoparibSensitivity/ResponseCIViC BEID10856
VEGFA Overexpression of VEGF121BevacizumabSensitivity/ResponseCIViC BEID9297
CDKN2A LossLetrozole + PalbociclibSensitivity/ResponseCIViC CEID1765

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
Atlas version
v1.1.2
BioBTree
v2.0.2

Sources 73

This page pulls from 73 datasets indexed by BioBTree:

alphafoldantibodybgeebgee_evidencebindingdbbiogrid_interactionbrendabrenda_kineticscellosauruschembl_activitychembl_assaychembl_documentchembl_moleculechembl_targetciviccivic_evidenceclingen_dosageclinical_trialsclinvarctd_gene_interactiondbsnpdepmapdiamond_similaritydoidefoensemblentrezesm2_similarityfantom5_genefantom5_promotergenccgenerifgogtopdbgtopdb_interactiongwasgwas_studyhgncintactinterprointogenmedgenmeshmimmondomondochildmondoparentncitorphanetpatentpatent_compoundpdbpfampharmgkb_clinicalpharmgkb_genepharmgkb_guidelinepharmgkb_variantpubchempubchem_activitypubchem_assayreactomerefseqrhearnacentralsctidscxa_expressionscxa_gene_experimentsignorstring_interactiontranscriptufeatureumlsuniprot