title: Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer.
abstract: Prostate cancer is characterized by its dependence on androgen receptor (AR) and frequent activation of PI3K signaling. We find that AR transcriptional output is decreased in human and murine tumors with PTEN deletion and that PI3K pathway inhibition activates AR signaling by relieving feedback inhibition of HER kinases. Similarly, AR inhibition activates AKT signaling by reducing levels of the AKT phosphatase PHLPP. Thus, these two oncogenic pathways cross-regulate each other by reciprocal feedback. Inhibition of one activates the other, thereby maintaining tumor cell survival. However, combined pharmacologic inhibition of PI3K and AR signaling caused near-complete prostate cancer regressions in a Pten-deficient murine prostate cancer model and in human prostate cancer xenografts, indicating that both pathways coordinately support survival.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Brett S
authors.initials: BS
authors.lastname: Carver
authors.forename: Caren
authors.initials: C
authors.lastname: Chapinski
authors.forename: John
authors.initials: J
authors.lastname: Wongvipat
authors.forename: Haley
authors.initials: H
authors.lastname: Hieronymus
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Sarat
authors.initials: S
authors.lastname: Chandarlapaty
authors.forename: Vivek K
authors.initials: VK
authors.lastname: Arora
authors.forename: Carl
authors.initials: C
authors.lastname: Le
authors.forename: Jason
authors.initials: J
authors.lastname: Koutcher
authors.forename: Howard
authors.initials: H
authors.lastname: Scher
authors.forename: Peter T
authors.initials: PT
authors.lastname: Scardino
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000726:Androgen Antagonists; D009687:Nuclear Proteins; D051059:PTEN Phosphohydrolase; D058539:Phosphatidylinositol 3-Kinase; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010749:Phosphoprotein Phosphatases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011944:Receptors, Androgen; C410798:AR protein, human; C489428:Myc protein, mouse; C400601:PHLPP1 protein, human; C494929:PTEN protein, human; C487757:Pten protein, mouse