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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • González-Billalabeitia, E; Seitzer, N; Song, SJ; Song, MS; 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, PP

Published Date

  • August 2014

Published In

Volume / Issue

  • 4 / 8

Start / End Page

  • 896 - 904

PubMed ID

  • 24866151

Pubmed Central ID

  • 24866151

Electronic International Standard Serial Number (EISSN)

  • 2159-8290

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-13-0230

Language

  • eng

Conference Location

  • United States