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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.
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.
What 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.
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.
It separates two explanations that are usually run together. Some of the difference in prostate cancer outcomes by race is in the tumour genome and persists when access to the same centre is held constant, and some of it tracks with income rather than with ancestry, so equalising access alone would not eliminate the gap.
PSMA PET-CT is the preferred staging investigation for high-risk prostate cancer and for biochemical recurrence, though most treatment trials were designed with conventional imaging.
It is the evidence behind using PSMA PET when PSA rises after treatment, and it quantifies the limit that matters most: below PSA 0.5 ng/mL, where salvage radiotherapy works best, the scan is negative in nearly two men in three, so a negative scan is not a reason to wait.
It is the quantitative answer to why prostate cancer has so few targeted therapies. The common events are not druggable, the druggable ones are individually rare, and no trial can be powered on a driver present in 2% of men without an international basket.
It is the reason a prostate cancer fusion frequency quoted without an ancestry is unsafe. In this cohort the founder event that defines almost half of Western tumours is uncommon, and the fusion-negative, CHD1-deleted route dominates instead.
The genomic definition of advanced prostate cancer, and the evidence that made molecular testing standard in it. The 19.3 percent DNA repair figure is the direct ancestor of PROfound, TRITON3, PROpel and TALAPRO-2, and the 8 percent germline figure is why a tumour result in this disease has implications for a man's relatives.
The reference classification of prostate cancer as it presents, and the source of the two numbers that drive most molecular treatment decisions in the disease: a quarter with a PI3K or MAPK lesion, which is the rationale for capivasertib in PTEN-deficient disease, and a fifth with DNA repair inactivation, which is the rationale for PARP inhibitors.
It established the fusion-negative side of the prostate cancer taxonomy and made SPOP the disease's signature point mutation, in a ubiquitin ligase adaptor rather than in a kinase, which is part of why prostate cancer has so few druggable drivers.
Shares The TMPRSS2-ERG rearrangement, ERG expression and prostate cancer outcomes: a cohort study and meta-analysis, Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer, Whole-genome and transcriptome sequencing of prostate cancer identifies new genetic alterations driving disease progression, The long tail of oncogenic drivers in prostate cancer.
Shares The TMPRSS2-ERG rearrangement, ERG expression and prostate cancer outcomes: a cohort study and meta-analysis, Whole-genome and transcriptome sequencing of prostate cancer identifies new genetic alterations driving disease progression, TMPRSS2-ERG fusion (and the other ETS rearrangements), Integrative genomic profiling of human prostate cancer.
Shares Differences in prostate cancer genomes by self-reported race, Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer, The long tail of oncogenic drivers in prostate cancer, The mutational landscape of lethal castration-resistant prostate cancer.
Shares Accuracy of gallium-68 PSMA-11 PET in localising recurrent prostate cancer: a prospective single-arm clinical trial, Prostate-specific membrane antigen expression in normal and malignant human tissues, proPSMA: PSMA PET-CT versus conventional imaging for staging high-risk prostate cancer, Lutetium-177 vipivotide tetraxetan.
Shares The TMPRSS2-ERG rearrangement, ERG expression and prostate cancer outcomes: a cohort study and meta-analysis, Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer, Whole-genome and transcriptome sequencing of prostate cancer identifies new genetic alterations driving disease progression, SPOP mutation.
Shares Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer, SPOP mutation, The long tail of oncogenic drivers in prostate cancer, TCGA: the molecular taxonomy of primary prostate cancer.
Shares AR amplification (gene and upstream enhancer), Androgen receptor signalling, Abiraterone acetate, Enzalutamide.
Shares Darolutamide, Apalutamide, Talazoparib, Niraparib.