AR

Overview

AR (Androgen Receptor) is a ligand-activated transcription factor and the central driver of prostate cancer growth. AR alterations — including point mutations, amplification, enhancer amplification, and splice variants (ARv7) — mediate resistance to androgen deprivation and AR-directed therapies. AR expression is markedly reduced in neuroendocrine prostate cancer (NEPC).

Alterations observed in the corpus

  • AR oncogenic mutations (H875Y, T878A), gene amplification, enhancer region amplification, and ARv7 splice variant expression detected across multiple prostate cancer patient-derived xenografts (PDXs) in an integrative multi-omic analysis (44 PDXs from 38 patients) PMID:38488813.
  • AR expression significantly reduced in NEPC vs. adenocarcinoma PDXs (P = 4 x 10^-9); AR-negative status is a defining feature of neuroendocrine lineage plasticity PMID:38488813.
  • AR alterations identified as recurrent post-treatment changes and associated with Gleason score and metastasis patterns in PRAD in the MSK-CHORD real-world cohort (n=42,655 patients) PMID:39506116.
  • Identified as somatically altered in integrative genomic profiling of prostate cancer (MSKCC cohort) PMID:20579941
  • Gains of the AR gene are noted as a common prostate cancer alteration in a WES study of 112 prostate tumors PMID:22610119
  • AR amplifications and mutations detected in prostate cancer WES of 112 tumors (Michigan cohort), with AR activity linked to ETS fusion status PMID:22722839
  • Amplification in MSK-PCa2 (mirrors ~50% of CRPC); silenced in MSK-PCa1; high-level expression with AR target-gene programs in MSK-PCa2/PCa7 prostate cancer cell lines PMID:25201530
  • Amplification and hotspot mutations (T878A, W742C, L702H, and novel mutations) in ~62.7% of mCRPC cases; AR pathway aggregate 71.3%; AR-V7 splice variant detectable in most pre-abiraterone/enzalutamide cases PMID:26000489
  • Mutation/amplification essentially absent in primary prostate cancer but frequent in mCRPC; AR-V7 and other splice variants detectable at low levels in primary tumors (TCGA prostate cohort) PMID:26544944
  • Focal amplification, activating point mutations, and ARv7 splice variant common in CRPC-Adeno but largely absent/low-level in CRPC-NE; AR signaling attenuated in CRPC-NE as part of lineage plasticity toward neuroendocrine differentiation PMID:26855148
  • AR amplification or mutation in 63% of men with mCRPC (n=56 men with WES); 88% of patients had tumors with robust AR transcriptional activity despite extensive prior androgen-suppressive therapy; AR activity was inversely correlated with cell cycle progression (CCP) score (r = -0.33, P < 0.001) PMID:26928463
  • AR: actionable alteration identified in salivary duct carcinoma (SDCA) by NGS-guided clinical sequencing in recurrent/metastatic head and neck cancer PMID:27442865
  • Mutated in 18% of PRAD patients (vs 1% in TCGA); recurrent acquired-resistance hotspots L702H and H875Y (10 patients each), detected via MSK-IMPACT pan-cancer profiling (n=10,945) PMID:28481359
  • AR altered in 63/500 metastatic cancer patients (12.6%) in the MET500 pan-cancer cohort, strongly tied to PRAD PMID:28783718
  • AR amplification and resistance mutations (F877L conferring resistance to enzalutamide/apalutamide; H875Y conferring resistance to flutamide) enriched in mCRPC; 4% of metastatic noncastrate tumors already carried AR alterations, consistent with subclinical transition to castration resistance PMID:28825054
  • AR is an established driver confirmed in metastatic prostate cancer with metastasis-vs-primary enrichment quantified across 1,013 prostate cancers (prad_p1000). PMID:29610475

Cancer types (linked)

Co-occurrence and mutual exclusivity

  • AR activation co-occurs with PTEN loss, TP53 mutations, and RB1 loss as part of the dominant driver alteration landscape in prostate cancer PDXs (91% of PDXs had oncogenic alterations in AR, RB1, TP53, or PTEN) PMID:38488813.
  • AR expression is mutually exclusive with neuroendocrine marker upregulation (AURKA/MYCN axis) in the NEPC phenotype PMID:38488813.

Therapeutic relevance

  • PDX organoid assays demonstrated activity of bicalutamide and enzalutamide in AR-expressing models; PDXs were used to test cisplatin, paclitaxel, cabazitaxel, and niraparib sensitivity across lineage states PMID:38488813.
  • ARv7 expression independently drives resistance to enzalutamide; its relationship to de novo AR activity vs. treatment selection remains under investigation PMID:38488813.

Open questions

  • Whether ARv7 can independently drive prostate cancer (versus being a resistance passenger) remains unresolved in the corpus PMID:38488813.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:20579941

This page was processed by crosslinker on 2026-05-14. - PMID:22610119

This page was processed by crosslinker on 2026-05-14. - PMID:22722839

This page was processed by crosslinker on 2026-05-14. - PMID:25201530

This page was processed by crosslinker on 2026-05-14. - PMID:26000489

This page was processed by crosslinker on 2026-05-14. - PMID:26544944

This page was processed by wiki-cli on 2026-05-14. - PMID:26855148

This page was processed by wiki-cli on 2026-05-14. - PMID:26928463

This page was processed by entity-page-writer on 2026-05-15. - PMID:27442865

This page was processed by wiki-cli on 2026-05-14. - PMID:28481359

This page was processed by entity-page-writer on 2026-05-15. - PMID:28783718

This page was processed by wiki-cli on 2026-05-15. - PMID:28825054

This page was processed by wiki-cli on 2026-05-15. - PMID:29610475

This page was processed by wiki-cli on 2026-05-15.