{"entity":{"id":"ar-ligand-binding-domain-mutation","kind":"biomarker","name":"AR ligand-binding-domain mutation (L702H, W742C, H875Y, T878A, F877L)","aka":["AR mutation","androgen receptor mutation","L702H","T878A","T877A","H875Y","F877L","F876L","W742C","AR LBD mutation"],"tldr":"A change in the part of the androgen receptor that hormone drugs attach to. Depending on which change it is, another hormone the man is already taking can switch the receptor on, or the blocking drug can start behaving as an activating one.","summary":"Androgen receptor mutations in this domain were first described in metastatic androgen-independent prostate cancer, where 5 of 10 men carried one and two of the mutant receptors could be activated by progesterone and by oestrogen in transfected cells (Taplin 1995). They are almost entirely a property of treated disease: cBioPortal records AR mutation in 61 of 444 samples (13.7%) in prad_su2c_2019 and 27 of 150 (18.0%) in prad_su2c_2015, against 2 of 494 (0.4%) in the TCGA primary cohort, where neither record falls in the ligand-binding domain at all. The spectrum is narrow and it tracks the treatment. In prad_su2c_2019 (72 mutation records): L702H 17, T878A 15, H875Y 11, W742C 8, W742L 4, F877L 3. L702H makes the receptor responsive to glucocorticoid, which matters because abiraterone is given with prednisone or prednisolone; T878A and H875Y open the pocket to progestogens and older antiandrogens; F877L converts enzalutamide and apalutamide from antagonists into agonists. Plasma detects compound and polyclonal combinations that a single biopsy cannot (Tukachinsky 2021).","asOf":"2026-09-25","links":[{"label":"Taplin et al., N Engl J Med 1995: androgen-receptor gene mutation in metastatic androgen-independent prostate cancer (10 patients)","url":"https://doi.org/10.1056/NEJM199505253322101"},{"label":"Tukachinsky et al., Clin Cancer Res 2021: circulating tumour DNA profiling in 3,334 men with advanced prostate cancer, including 1,674 TRITON screening samples","url":"https://doi.org/10.1158/1078-0432.CCR-20-4805"},{"label":"cBioPortal study prad_su2c_2019 (SU2C/PCF Dream Team, PNAS 2019; 444 metastatic castration-resistant samples from 429 patients, whole exome)","url":"https://www.cbioportal.org/study/summary?id=prad_su2c_2019"}],"tags":["biomarker","resistance"],"related":["ar-amplification","ar-v7-splice-variant"],"cancers":["prostate","prostate-mcrpc"],"sections":[],"technologies":["cgp","liquid-biopsy"],"targets":["androgen-receptor","cyp17a1"],"drugs":[],"companies":[],"institutions":[],"pathways":["ar-signaling","resistance-routes-map"],"terms":["castration-resistance","resistance","cross-resistance","driver-mutation","ctdna"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-taplin-ar-mutation-androgen-independent-prostate-nejm-1995","paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004","paper-tukachinsky-ctdna-3334-advanced-prostate-ccr-2021"],"journals":[],"dependsOn":[],"notes":[],"target":"androgen-receptor","measurement":"sequencing-variant","scoringRule":{"text":"A missense substitution in the AR ligand-binding domain on tumour or plasma sequencing, reported by specific residue rather than as AR mutated, since the clinical meaning differs by allele and more than one allele is often present at once.","quote":"Point mutations in the androgen-receptor gene were identified in metastatic cells from 5 of the 10 patients examined... Functional studies of two of the mutant androgen receptors demonstrated that they could be activated by progesterone and estrogen.","source":"https://doi.org/10.1056/NEJM199505253322101","sourceLabel":"Taplin et al., New England Journal of Medicine 1995"},"thresholds":[],"definedBy":{"label":"Taplin et al., N Engl J Med 1995: mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer","url":"https://doi.org/10.1056/NEJM199505253322101"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"A report that says only that the androgen receptor is mutated has not answered the question. Which change it is decides whether a different hormone tablet is still worth trying, and whether a steroid being taken alongside could be feeding the cancer. It is a question for a specialist centre, because no approval depends on it."},"route":"/biomarkers/ar-ligand-binding-domain-mutation/","neighbours":{"biomarker":[{"id":"ar-amplification","kind":"biomarker","name":"AR amplification (gene and upstream enhancer)","route":"/biomarkers/ar-amplification/"},{"id":"ar-v7-splice-variant","kind":"biomarker","name":"AR-V7 splice variant","route":"/biomarkers/ar-v7-splice-variant/"}],"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/"}],"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"}],"target":[{"id":"androgen-receptor","kind":"target","name":"Androgen receptor","route":"/targets/androgen-receptor/"},{"id":"cyp17a1","kind":"target","name":"CYP17A1 (17-alpha-hydroxylase/17,20-lyase)","route":"/targets/cyp17a1/"}],"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/"}],"term":[{"id":"castration-resistance","kind":"term","name":"Castration-resistant prostate cancer (CRPC)","route":"/terms/castration-resistance/"},{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/"},{"id":"cross-resistance","kind":"term","name":"Cross-resistance","route":"/terms/cross-resistance/"},{"id":"driver-mutation","kind":"term","name":"Driver mutation","route":"/terms/driver-mutation/"},{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"}],"paper":[{"id":"paper-tukachinsky-ctdna-3334-advanced-prostate-ccr-2021","kind":"paper","name":"Genomic analysis of circulating tumour DNA in 3,334 patients with advanced prostate cancer identifies targetable BRCA alterations and AR resistance mechanisms","route":"/key-papers/paper-tukachinsky-ctdna-3334-advanced-prostate-ccr-2021/"},{"id":"paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004","kind":"paper","name":"Molecular determinants of resistance to antiandrogen therapy","route":"/key-papers/paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004/"},{"id":"paper-taplin-ar-mutation-androgen-independent-prostate-nejm-1995","kind":"paper","name":"Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer","route":"/key-papers/paper-taplin-ar-mutation-androgen-independent-prostate-nejm-1995/"}]}}