{"entity":{"id":"paper-carver-pi3k-ar-reciprocal-feedback-prostate-cancer-cell-2011","kind":"paper","name":"Reciprocal feedback regulation of PI3K and androgen receptor signalling in PTEN-deficient prostate cancer","aka":[],"tldr":"Two growth pathways in prostate cancer prop each other up: block one and the other switches on, which is why single drugs fail and the pair has to be blocked together.","summary":"Androgen receptor transcriptional output is decreased in human and murine prostate tumours with PTEN deletion, and PI3K pathway inhibition activates androgen receptor signalling by relieving feedback inhibition of the HER kinases. Conversely, androgen receptor inhibition activates AKT signalling by reducing levels of the AKT phosphatase PHLPP. The two oncogenic pathways therefore cross-regulate each other by reciprocal feedback, and inhibiting one activates the other, maintaining tumour cell survival. Combined pharmacological inhibition of PI3K and androgen receptor signalling caused near-complete prostate cancer regressions in a Pten-deficient murine prostate cancer model and in human prostate cancer xenografts.","asOf":"2026-09-25","links":[{"label":"Carver et al., Cancer Cell 2011: reciprocal feedback between PI3K and androgen receptor signalling in PTEN-deficient prostate cancer","url":"https://doi.org/10.1016/j.ccr.2011.04.008"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/21575859/"}],"tags":[],"related":[],"cancers":["prostate","prostate-mcrpc"],"sections":[],"technologies":[],"targets":["pten","akt","androgen-receptor","pik3ca"],"drugs":[],"companies":[],"institutions":[],"pathways":["pi3k-akt-mtor","ar-signaling","rtk-activation","resistance-routes-map"],"terms":["resistance","castration-resistance"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["cancer-cell"],"dependsOn":[],"notes":[],"journal":"Cancer Cell","year":2011,"doi":"10.1016/j.ccr.2011.04.008","pmid":"21575859","authors":"Carver BS, Chapinski C, Wongvipat J, et al.","paperType":"basic","findings":["Androgen receptor output is reduced in PTEN-deleted prostate tumours.","PI3K inhibition reactivates androgen receptor signalling by relieving feedback on the HER kinases.","Androgen receptor inhibition activates AKT by reducing the phosphatase PHLPP.","Combined inhibition produced near-complete regressions in Pten-deficient models and xenografts."],"whatItMeans":"It is the reason every prostate PI3K or AKT trial gives the drug with abiraterone rather than alone, and the reason PTEN loss is used to select for those combinations rather than as a general prognostic marker.","caveats":["Mouse models and xenografts; the human confirmation is the randomised trial, which met only one of its two co-primary endpoints.","The feedback is described for PTEN-deficient disease and may not generalise.","Toxicity of dual blockade in men has proved a limiting factor the models did not predict."],"changedPractice":false},"route":"/key-papers/paper-carver-pi3k-ar-reciprocal-feedback-prostate-cancer-cell-2011/","neighbours":{"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/"}],"target":[{"id":"akt","kind":"target","name":"AKT","route":"/targets/akt/"},{"id":"androgen-receptor","kind":"target","name":"Androgen receptor","route":"/targets/androgen-receptor/"},{"id":"pik3ca","kind":"target","name":"PIK3CA / PI3K-alpha","route":"/targets/pik3ca/"},{"id":"pten","kind":"target","name":"PTEN","route":"/targets/pten/"}],"pathway":[{"id":"ar-signaling","kind":"pathway","name":"Androgen receptor signalling","route":"/pathways/ar-signaling/"},{"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/"},{"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":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"}],"journal":[{"id":"cancer-cell","kind":"journal","name":"Cancer Cell","route":"/journals/cancer-cell/"}],"biomarker":[{"id":"pten-alteration","kind":"biomarker","name":"PTEN alteration (sequencing) and PTEN loss (IHC)","route":"/biomarkers/pten-alteration/"}]}}