title: Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition.
abstract: Prostate cancer is the most prevalent cancer in males, and treatment options are limited for advanced forms of the disease. Loss of the PTEN and TP53 tumor suppressor genes is commonly observed in prostate cancer, whereas their compound loss is often observed in advanced prostate cancer. Here, we show that PARP inhibition triggers a p53-dependent cellular senescence in a PTEN-deficient setting in the prostate. Surprisingly, we also find that PARP-induced cellular senescence is morphed into an apoptotic response upon compound loss of PTEN and p53. We further show that superactivation of the prosurvival PI3K-AKT signaling pathway limits the efficacy of a PARP single-agent treatment, and that PARP and PI3K inhibitors effectively synergize to suppress tumorigenesis in human prostate cancer cell lines and in a Pten/Trp53-deficient mouse model of advanced prostate cancer. Our findings, therefore, identify a combinatorial treatment with PARP and PI3K inhibitors as an effective option for PTEN-deficient prostate cancer.
  
  
  CONCLUSIONS
  The paucity of therapeutic options in advanced prostate cancer displays an urgent need for the preclinical assessment of novel therapeutic strategies. We identified differential therapeutic vulnerabilities that emerge upon the loss of both PTEN and p53, and observed that combined inhibition of PARP and PI3K provides increased efficacy in hormone-insensitive advanced prostate cancer.
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School; Department of Medicine; Divisions of On leave of absence: Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Murcia, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: González-Billalabeitia
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School; Department of Medicine; Divisions of.
authors.forename: Nina
authors.initials: N
authors.lastname: Seitzer
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School; Department of Medicine; Divisions of.
authors.forename: Su Jung
authors.initials: SJ
authors.lastname: Song
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School; Department of Medicine; Divisions of.
authors.forename: Min Sup
authors.initials: MS
authors.lastname: Song
authors.affiliation: Hematology/Oncology and Signal Transduction, Department of Medicine; Department of Systems Biology, Harvard Medical School;
authors.forename: Akash
authors.initials: A
authors.lastname: Patnaik
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School; Department of Medicine; Divisions of.
authors.forename: Xue-Song
authors.initials: XS
authors.lastname: Liu
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School; Department of Medicine; Divisions of.
authors.forename: Mirjam T
authors.initials: MT
authors.lastname: Epping
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School; Department of Medicine; Divisions of.
authors.forename: Antonella
authors.initials: A
authors.lastname: Papa
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School; Department of Medicine; Divisions of.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Hobbs
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School; Department of Medicine; Divisions of.
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School; Department of Medicine; Divisions of.
authors.forename: Andrea
authors.initials: A
authors.lastname: Lunardi
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School; Department of Medicine; Divisions of.
authors.forename: Christopher
authors.initials: C
authors.lastname: Ng
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School; Department of Medicine; Divisions of.
authors.forename: Kaitlyn A
authors.initials: KA
authors.lastname: Webster
authors.affiliation: Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Medical Center; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston;
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.affiliation: Department of Pathology, Brigham and Women's Hospital; Center for Molecular Oncologic Pathology; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts; and.
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.affiliation: Department of Systems Biology, Harvard Medical School;
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School; Department of Medicine; Divisions of Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Medical Center;
authors.forename: Caterina
authors.initials: C
authors.lastname: Nardella
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School; Department of Medicine; Divisions of Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Medical Center;
authors.forename: John G
authors.initials: JG
authors.lastname: Clohessy
authors.affiliation: Signal Transduction, Department of Medicine; Department of Systems Biology, Harvard Medical School;
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School; Department of Medicine; Divisions of ppandolf@bidmc.harvard.edu.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects; D053492:Elafin / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D053492:Elafin; C506806:PI3 protein, human; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D011065:Poly(ADP-ribose) Polymerases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human