{"entity":{"id":"paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004","kind":"paper","name":"Molecular determinants of resistance to antiandrogen therapy","aka":["Chen 2004","AR overexpression antiandrogen resistance","Sawyers 2004 androgen receptor"],"tldr":"This study found the one change that always happened when prostate cancer became resistant to hormone-blocking drugs: the cell made more androgen receptor. With enough of it, the drugs that were meant to block the receptor started switching it on instead.","summary":"Charles Chen and colleagues in Charles Sawyers's laboratory profiled isogenic prostate cancer xenografts before and after they became resistant to antiandrogen therapy. Across the models, a modest increase in androgen receptor messenger RNA was the only change consistently associated with resistance, and it was both necessary and sufficient to convert hormone-sensitive growth into hormone-refractory growth.\n\nThe mechanistic half of the paper matters as much as the observation. At high receptor levels, antagonists behaved as agonists, and the switch tracked a change in which coactivators and corepressors were recruited to the promoters of androgen receptor target genes. That is the biology behind antiandrogen withdrawal response, and it is the design brief that produced enzalutamide, which came out of the same laboratory.","asOf":"2026-09-25","links":[{"label":"Nat Med 2004","url":"https://doi.org/10.1038/nm972"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/14702632/"}],"tags":["prostate-evidence"],"related":["paper-visakorpi-androgen-receptor-amplification-nat-genet-1995","paper-attard-abiraterone-phase-1-cyp17-jco-2008","prostate-roadmap"],"cancers":["prostate","prostate-mcrpc"],"sections":["hormonal","targeted-therapy","drug-discovery"],"technologies":[],"targets":["androgen-receptor"],"drugs":["enzalutamide","bicalutamide"],"companies":[],"institutions":[],"pathways":["ar-signaling","resistance-routes-map","transcription-addiction"],"terms":["castration-resistance","resistance","adt"],"trials":[],"people":["charles-sawyers"],"bottlenecks":["b-resistance","b-preclinical-models"],"keyPapers":[],"journals":["nature-medicine"],"dependsOn":[],"notes":[],"journal":"Nature Medicine","year":2004,"doi":"10.1038/nm972","pmid":"14702632","authors":"Chen CD, Welsbie DS, Tran C, et al.","paperType":"basic","findings":["A modest increase in androgen receptor messenger RNA was the only change consistently associated with the development of resistance to antiandrogen therapy across isogenic xenograft models.","The increase in androgen receptor messenger RNA and protein was both necessary and sufficient to convert growth from hormone-sensitive to hormone-refractory, and depended on a functional ligand-binding domain.","Androgen receptor antagonists showed agonistic activity in cells with increased receptor levels, an antagonist-agonist conversion associated with altered recruitment of coactivators and corepressors."],"whatItMeans":"The design specification for the second-generation antiandrogens. A drug for castration-resistant prostate cancer has to stay an antagonist when the receptor is abundant, which is what enzalutamide, apalutamide and darolutamide were engineered to do and what bicalutamide fails to do.","caveats":["Xenograft models, not patients; the human confirmation came from receptor amplification in recurrent tumours and from the activity of the drugs the paper predicted.","Receptor overexpression is one route to resistance among several; ligand-binding domain mutations, splice variants and loss of androgen receptor dependence altogether are others.","The dependence on a functional ligand-binding domain is exactly what AR-V7 lacks, which is why the drugs that followed do not work in AR-V7-positive disease (paper-antonarakis-ar-v7-resistance-nejm-2014)."],"changedPractice":false},"route":"/key-papers/paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004/","neighbours":{"paper":[{"id":"paper-scher-affirm-enzalutamide-nejm-2012","kind":"paper","name":"AFFIRM: increased survival with enzalutamide in prostate cancer after chemotherapy","route":"/key-papers/paper-scher-affirm-enzalutamide-nejm-2012/"},{"id":"paper-antonarakis-ar-v7-resistance-nejm-2014","kind":"paper","name":"AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer","route":"/key-papers/paper-antonarakis-ar-v7-resistance-nejm-2014/"},{"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-attard-abiraterone-phase-1-cyp17-jco-2008","kind":"paper","name":"Phase 1 trial of abiraterone acetate confirms that castration-resistant prostate cancer commonly remains hormone driven","route":"/key-papers/paper-attard-abiraterone-phase-1-cyp17-jco-2008/"},{"id":"paper-teply-restore-bipolar-androgen-therapy-lancet-oncol-2018","kind":"paper","name":"RESTORE: bipolar androgen therapy after progression on enzalutamide in metastatic castration-resistant prostate cancer","route":"/key-papers/paper-teply-restore-bipolar-androgen-therapy-lancet-oncol-2018/"}],"roadmap":[{"id":"prostate-roadmap","kind":"roadmap","name":"Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch","route":"/roadmaps/prostate-roadmap/"}],"cancer":[{"id":"prostate-mcrpc","kind":"cancer","name":"Metastatic castration-resistant prostate cancer","route":"/cancers/prostate-mcrpc/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"section":[{"id":"drug-discovery","kind":"section","name":"Drug Discovery Platforms","route":"/fronts/drug-discovery/"},{"id":"hormonal","kind":"section","name":"Hormonal Therapy","route":"/fronts/hormonal/"},{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"target":[{"id":"androgen-receptor","kind":"target","name":"Androgen receptor","route":"/targets/androgen-receptor/"}],"drug":[{"id":"bicalutamide","kind":"drug","name":"Bicalutamide","route":"/drugs/bicalutamide/"},{"id":"enzalutamide","kind":"drug","name":"Enzalutamide","route":"/drugs/enzalutamide/"}],"pathway":[{"id":"ar-signaling","kind":"pathway","name":"Androgen receptor signalling","route":"/pathways/ar-signaling/"},{"id":"resistance-routes-map","kind":"pathway","name":"Resistance routes: how a blocked pathway comes back","route":"/pathways/resistance-routes-map/"},{"id":"transcription-addiction","kind":"pathway","name":"Transcriptional machinery & addiction","route":"/pathways/transcription-addiction/"}],"term":[{"id":"adt","kind":"term","name":"Androgen deprivation therapy (ADT)","route":"/terms/adt/"},{"id":"bipolar-androgen-therapy","kind":"term","name":"Bipolar androgen therapy (BAT)","route":"/terms/bipolar-androgen-therapy/"},{"id":"castration-resistance","kind":"term","name":"Castration-resistant prostate cancer (CRPC)","route":"/terms/castration-resistance/"},{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"}],"person":[{"id":"charles-sawyers","kind":"person","name":"Charles L. Sawyers","route":"/people/charles-sawyers/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-preclinical-models","kind":"bottleneck","name":"Lab models that fail to predict what happens in patients","route":"/bottlenecks/b-preclinical-models/"}],"journal":[{"id":"nature-medicine","kind":"journal","name":"Nature Medicine","route":"/journals/nature-medicine/"}],"idea":[{"id":"idea-prostate-bipolar-androgen-therapy-phase-3-on-pfs2","kind":"idea","name":"Take high-dose testosterone to phase 3, with progression-free survival through the second line as the primary endpoint","route":"/ideas/idea-prostate-bipolar-androgen-therapy-phase-3-on-pfs2/"}],"biomarker":[{"id":"ar-ligand-binding-domain-mutation","kind":"biomarker","name":"AR ligand-binding-domain mutation (L702H, W742C, H875Y, T878A, F877L)","route":"/biomarkers/ar-ligand-binding-domain-mutation/"}]}}