{"entity":{"id":"prostate-cancer-signalling","kind":"pathway","name":"Prostate cancer (KEGG map)","aka":["KEGG hsa05215","Prostate cancer"],"tldr":"KEGG's prostate cancer map centres on the androgen receptor, the hormone switch that prostate cells depend on, plus loss of PTEN and NKX3.1 that lets PI3K/AKT growth signalling run free. Hormone therapy, AR antagonists and now AKT inhibitors act on these two arms.","summary":"The KEGG prostate cancer map (hsa05215) draws the androgen receptor (AR) as the central node. Testosterone is converted by SRD5A2 to dihydrotestosterone, which releases AR from HSP90 chaperones so it enters the nucleus and, with co-activators (CREBBP, EP300, NCOA family), switches on target genes such as KLK3 (PSA), TMPRSS2 and, through the TMPRSS2-ERG fusion, the ERG oncogene. During androgen deprivation the map shows how AR signalling is re-established: AR gene amplification, AR mutations that respond to other ligands, altered co-activator activity and growth-factor cross-talk. The second arm is growth-factor signalling: EGFR, ERBB2, IGF1R, FGFR and PDGFR feed PI3K to AKT to mTOR, and AKT both stabilises AR output and inhibits FOXO and BAD. PTEN loss, which is very common, and NKX3.1 loss lower p27 (CDKN1B) and remove restraint on the cell cycle, while MDM2 activation by AKT lowers p53. KEGG also draws GSTP1 silencing, which removes carcinogen detoxification in prostatic intraepithelial neoplasia, and FOLH1 (PSMA), the surface protein now used for imaging and radioligand therapy. Watson, Arora and Sawyers, Nat Rev Cancer, 2015 (doi:10.1038/nrc4016) review how castration-resistant tumours restore AR signalling through amplification, ligand-binding-domain mutations (such as F877L under enzalutamide), constitutively active splice variants like AR-V7, intratumoural androgen synthesis and glucocorticoid receptor substitution, and how PTEN loss and lineage plasticity provide AR-independent escape.\n\nWhat drugs do about it: androgen deprivation (GnRH agonists or antagonists) removes the ligand; abiraterone blocks CYP17-dependent androgen synthesis; the AR antagonists enzalutamide, apalutamide and darolutamide stop AR binding DNA even when amplified; the AKT inhibitor capivasertib with abiraterone is approved for PTEN-deficient metastatic castration-resistant disease; and the PSMA radioligand lutetium-177 vipivotide tetraxetan (Pluvicto) delivers radiation to FOLH1-expressing cells after AR pathway inhibitors.","asOf":"2026-09-10","links":[{"label":"KEGG map hsa05215","url":"https://www.kegg.jp/pathway/hsa05215"},{"label":"Review: Emerging mechanisms of resistance to AR inhibitors in prostate cancer","url":"https://doi.org/10.1038/nrc4016"}],"tags":[],"related":["ar-signaling","pi3k-akt-mtor"],"cancers":["prostate"],"sections":[],"technologies":[],"targets":["androgen-receptor","egfr","akt","mdm2","psma"],"drugs":["enzalutamide","abiraterone","apalutamide","darolutamide","capivasertib","pluvicto","olaparib","niraparib","talazoparib"],"companies":[],"institutions":[],"pathways":["ar-signaling","pi3k-akt-mtor","rtk-activation","p53-cell-cycle","lineage-plasticity-neuroendocrine"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"analogy":"The androgen receptor is an engine that runs on testosterone. Cutting the fuel (androgen deprivation) works until the tumour fits a bigger tank (AR amplification) or an engine that runs on anything (AR mutations and splice variants). Enzalutamide and its cousins clamp the engine itself; capivasertib deals with the separate PI3K/AKT motor that PTEN loss switches on.","nodes":[{"id":"androgen","label":"Testosterone to DHT (SRD5A2)","x":20,"y":6},{"id":"ar","label":"Androgen receptor (amplified, mutated)","x":20,"y":30,"targetId":"androgen-receptor"},{"id":"coact","label":"Co-activators (CBP/p300, NCOA)","x":50,"y":20},{"id":"argenes","label":"KLK3 (PSA), TMPRSS2-ERG","x":20,"y":56},{"id":"rtk","label":"EGFR, IGF1R, FGFR, PDGFR","x":80,"y":6,"targetId":"egfr"},{"id":"pten","label":"PTEN, NKX3.1 (lost)","x":95,"y":30},{"id":"pi3k","label":"PI3K / AKT / mTOR","x":75,"y":40,"targetId":"akt"},{"id":"p27","label":"p27 (CDKN1B)","x":75,"y":62},{"id":"mdm2","label":"MDM2 to p53","x":95,"y":62,"targetId":"mdm2"},{"id":"psma","label":"FOLH1 (PSMA)","x":50,"y":78,"targetId":"psma"},{"id":"out","label":"Growth, survival, castration resistance","x":50,"y":95}],"edges":[{"from":"androgen","to":"ar","type":"activates"},{"from":"coact","to":"ar","type":"activates"},{"from":"ar","to":"argenes","type":"activates"},{"from":"argenes","to":"out","type":"activates"},{"from":"rtk","to":"pi3k","type":"activates"},{"from":"pten","to":"pi3k","type":"inhibits"},{"from":"pi3k","to":"ar","type":"activates"},{"from":"pi3k","to":"p27","type":"inhibits"},{"from":"pi3k","to":"mdm2","type":"activates"},{"from":"p27","to":"out","type":"inhibits"},{"from":"mdm2","to":"out","type":"activates"},{"from":"psma","to":"out","type":"activates"}],"interventions":["Androgen deprivation (GnRH agonists or antagonists) combined with an AR pathway inhibitor: enzalutamide, apalutamide, darolutamide or abiraterone (CYP17 inhibitor)","AKT inhibitor capivasertib plus abiraterone for PTEN-deficient metastatic castration-resistant prostate cancer","PSMA radioligand therapy (lutetium-177 vipivotide tetraxetan, Pluvicto) for PSMA-positive disease after AR pathway inhibitors","PARP inhibitors (olaparib, niraparib, talazoparib) with an AR pathway inhibitor for BRCA-altered disease","Docetaxel or cabazitaxel chemotherapy; radiotherapy or prostatectomy for localised disease"]},"route":"/pathways/prostate-cancer-signalling/","neighbours":{"pathway":[{"id":"ar-signaling","kind":"pathway","name":"Androgen receptor signalling","route":"/pathways/ar-signaling/"},{"id":"lineage-plasticity-neuroendocrine","kind":"pathway","name":"Lineage plasticity & neuroendocrine transformation","route":"/pathways/lineage-plasticity-neuroendocrine/"},{"id":"p53-cell-cycle","kind":"pathway","name":"p53 / RB / cell-cycle checkpoint","route":"/pathways/p53-cell-cycle/"},{"id":"pi3k-akt-mtor","kind":"pathway","name":"PI3K / AKT / mTOR","route":"/pathways/pi3k-akt-mtor/"},{"id":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/"}],"cancer":[{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"target":[{"id":"akt","kind":"target","name":"AKT","route":"/targets/akt/"},{"id":"androgen-receptor","kind":"target","name":"Androgen receptor","route":"/targets/androgen-receptor/"},{"id":"cdkn1b","kind":"target","name":"CDKN1B","route":"/targets/cdkn1b/"},{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"ep300","kind":"target","name":"EP300","route":"/targets/ep300/"},{"id":"klk3","kind":"target","name":"KLK3","route":"/targets/klk3/"},{"id":"mdm2","kind":"target","name":"MDM2","route":"/targets/mdm2/"},{"id":"nkx3-1","kind":"target","name":"NKX3-1","route":"/targets/nkx3-1/"},{"id":"psma","kind":"target","name":"PSMA","route":"/targets/psma/"}],"drug":[{"id":"abiraterone","kind":"drug","name":"Abiraterone acetate","route":"/drugs/abiraterone/"},{"id":"apalutamide","kind":"drug","name":"Apalutamide","route":"/drugs/apalutamide/"},{"id":"capivasertib","kind":"drug","name":"Capivasertib","route":"/drugs/capivasertib/"},{"id":"darolutamide","kind":"drug","name":"Darolutamide","route":"/drugs/darolutamide/"},{"id":"enzalutamide","kind":"drug","name":"Enzalutamide","route":"/drugs/enzalutamide/"},{"id":"pluvicto","kind":"drug","name":"Lutetium-177 vipivotide tetraxetan","route":"/drugs/pluvicto/"},{"id":"niraparib","kind":"drug","name":"Niraparib","route":"/drugs/niraparib/"},{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"},{"id":"talazoparib","kind":"drug","name":"Talazoparib","route":"/drugs/talazoparib/"}],"paper":[{"id":"paper-fendler-psma-pet-biochemical-recurrence-jama-oncol-2019","kind":"paper","name":"Accuracy of gallium-68 PSMA-11 PET in localising recurrent prostate cancer: a prospective single-arm clinical trial","route":"/key-papers/paper-fendler-psma-pet-biochemical-recurrence-jama-oncol-2019/"},{"id":"paper-stopsack-prostate-genomes-by-race-ccr-2022","kind":"paper","name":"Differences in prostate cancer genomes by self-reported race","route":"/key-papers/paper-stopsack-prostate-genomes-by-race-ccr-2022/"},{"id":"paper-barbieri-spop-foxa1-med12-prostate-nat-genet-2012","kind":"paper","name":"Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer","route":"/key-papers/paper-barbieri-spop-foxa1-med12-prostate-nat-genet-2012/"},{"id":"paper-visakorpi-androgen-receptor-amplification-nat-genet-1995","kind":"paper","name":"In vivo amplification of the androgen receptor gene and progression of human prostate cancer","route":"/key-papers/paper-visakorpi-androgen-receptor-amplification-nat-genet-1995/"},{"id":"paper-taylor-integrative-genomic-profiling-cancer-cell-2010","kind":"paper","name":"Integrative genomic profiling of human prostate cancer","route":"/key-papers/paper-taylor-integrative-genomic-profiling-cancer-cell-2010/"},{"id":"paper-propsma-hofman-lancet-2020","kind":"paper","name":"proPSMA: PSMA PET-CT versus conventional imaging for staging high-risk prostate cancer","route":"/key-papers/paper-propsma-hofman-lancet-2020/"},{"id":"paper-silver-psma-expression-normal-malignant-tissues-ccr-1997","kind":"paper","name":"Prostate-specific membrane antigen expression in normal and malignant human tissues","route":"/key-papers/paper-silver-psma-expression-normal-malignant-tissues-ccr-1997/"},{"id":"paper-tomlins-tmprss2-ets-fusion-science-2005","kind":"paper","name":"Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer","route":"/key-papers/paper-tomlins-tmprss2-ets-fusion-science-2005/"},{"id":"paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015","kind":"paper","name":"SU2C-PCF: integrative clinical genomics of advanced prostate cancer","route":"/key-papers/paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015/"},{"id":"paper-tcga-molecular-taxonomy-primary-prostate-cell-2015","kind":"paper","name":"TCGA: the molecular taxonomy of primary prostate cancer","route":"/key-papers/paper-tcga-molecular-taxonomy-primary-prostate-cell-2015/"},{"id":"paper-armenia-long-tail-oncogenic-drivers-prostate-nat-genet-2018","kind":"paper","name":"The long tail of oncogenic drivers in prostate cancer","route":"/key-papers/paper-armenia-long-tail-oncogenic-drivers-prostate-nat-genet-2018/"},{"id":"paper-grasso-mutational-landscape-lethal-crpc-nature-2012","kind":"paper","name":"The mutational landscape of lethal castration-resistant prostate cancer","route":"/key-papers/paper-grasso-mutational-landscape-lethal-crpc-nature-2012/"},{"id":"paper-pettersson-tmprss2-erg-outcome-meta-analysis-cebp-2012","kind":"paper","name":"The TMPRSS2-ERG rearrangement, ERG expression and prostate cancer outcomes: a cohort study and meta-analysis","route":"/key-papers/paper-pettersson-tmprss2-erg-outcome-meta-analysis-cebp-2012/"},{"id":"paper-ren-chinese-prostate-whole-genome-eur-urol-2018","kind":"paper","name":"Whole-genome and transcriptome sequencing of prostate cancer identifies new genetic alterations driving disease progression","route":"/key-papers/paper-ren-chinese-prostate-whole-genome-eur-urol-2018/"}],"biomarker":[{"id":"ar-amplification","kind":"biomarker","name":"AR amplification (gene and upstream enhancer)","route":"/biomarkers/ar-amplification/"},{"id":"spop-mutation","kind":"biomarker","name":"SPOP mutation","route":"/biomarkers/spop-mutation/"},{"id":"tmprss2-erg-fusion","kind":"biomarker","name":"TMPRSS2-ERG fusion (and the other ETS rearrangements)","route":"/biomarkers/tmprss2-erg-fusion/"}]}}