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

TitleVulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition.
Publication TypeJournal Article
Year of Publication2014
AuthorsGonzález-Billalabeitia E, Seitzer N, Song SJung, Song MSup, Patnaik A, Liu X-S, Epping MT, Papa A, Hobbs RM, Chen M, Lunardi A, Ng C, Webster KA, Signoretti S, Loda M, Asara JM, Nardella C, Clohessy JG, Cantley LC, Pandolfi PPaolo
JournalCancer Discov
Volume4
Issue8
Pagination896-904
Date Published2014 Aug
ISSN2159-8290
KeywordsAnimals, Apoptosis, Cell Line, Tumor, Cellular Senescence, Elafin, Humans, Male, Mice, Molecular Targeted Therapy, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases, Prostatic Neoplasms, PTEN Phosphohydrolase, Tumor Suppressor Protein p53
Abstract

UNLABELLED: 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.

DOI10.1158/2159-8290.CD-13-0230
Alternate JournalCancer Discov
PubMed ID24866151
Grant List5P01CA120964-04 / CA / NCI NIH HHS / United States
R01 GM41890 / GM / NIGMS NIH HHS / United States
5P30CA006516-46 / CA / NCI NIH HHS / United States
RC2 CA147940-01 / CA / NCI NIH HHS / United States
Related Faculty: 
Massimo Loda, M.D.

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