Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition. Academic Article uri icon

Overview

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.

publication date

  • May 27, 2014

Research

keywords

  • Elafin
  • PTEN Phosphohydrolase
  • Poly(ADP-ribose) Polymerases
  • Prostatic Neoplasms
  • Tumor Suppressor Protein p53

Identity

PubMed Central ID

  • PMC4125493

Scopus Document Identifier

  • 84905493584

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-13-0230

PubMed ID

  • 24866151

Additional Document Info

volume

  • 4

issue

  • 8