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

ABSTRACT:

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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

SUBMITTER: Gonzalez-Billalabeitia E 

PROVIDER: S-EPMC4125493 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature