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

Enrique González-Billalabeitia, Nina Seitzer, Su Jung Song, Min Sup Song, Akash Patnaik, Xue Song Liu, Mirjam T. Epping, Antonella Papa, Robin M. Hobbs, Ming Chen, Andrea Lunardi, Christopher Ng, Kaitlyn A. Webster, Sabina Signoretti, Massimo Loda, John M. Asara, Caterina Nardella, John G. Clohessy, Lewis C Cantley, Pier Paolo Pandolfi

Research output: Contribution to journalArticleResearchpeer-review

49 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)896-904
Number of pages9
JournalCancer Discovery
Volume4
Issue number8
DOIs
Publication statusPublished - Aug 2014
Externally publishedYes

Cite this