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Cancer Discov. 2014 Aug;4(8):896-904. doi: 10.1158/2159-8290.CD-13-0230. Epub 2014 May 27.

Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition.

Author information

1
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.
2
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.
3
Hematology/Oncology and Signal Transduction, Department of Medicine; Department of Systems Biology, Harvard Medical School;
4
Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Medical Center; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston;
5
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.
6
Department of Systems Biology, Harvard Medical School;
7
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;
8
Signal Transduction, Department of Medicine; Department of Systems Biology, Harvard Medical School;
9
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.

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.

SIGNIFICANCE:

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.

PMID:
24866151
PMCID:
PMC4125493
DOI:
10.1158/2159-8290.CD-13-0230
[Indexed for MEDLINE]
Free PMC Article

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