Skip to main content

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

Publication ,  Journal Article
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 ...
Published in: Cancer Discov
August 2014

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

August 2014

Volume

4

Issue

8

Start / End Page

896 / 904

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Prostatic Neoplasms
  • Poly(ADP-ribose) Polymerases
  • Poly(ADP-ribose) Polymerase Inhibitors
  • PTEN Phosphohydrolase
  • Molecular Targeted Therapy
  • Mice
  • Male
  • Humans
  • Elafin
 

Citation

APA
Chicago
ICMJE
MLA
NLM
González-Billalabeitia, E., Seitzer, N., Song, S. J., Song, M. S., Patnaik, A., Liu, X.-S., … Pandolfi, P. P. (2014). Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition. Cancer Discov, 4(8), 896–904. https://doi.org/10.1158/2159-8290.CD-13-0230
González-Billalabeitia, Enrique, Nina Seitzer, Su Jung Song, Min Sup Song, Akash Patnaik, Xue-Song Liu, Mirjam T. Epping, et al. “Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition.Cancer Discov 4, no. 8 (August 2014): 896–904. https://doi.org/10.1158/2159-8290.CD-13-0230.
González-Billalabeitia E, Seitzer N, Song SJ, Song MS, Patnaik A, Liu X-S, et al. Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition. Cancer Discov. 2014 Aug;4(8):896–904.
González-Billalabeitia, Enrique, et al. “Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition.Cancer Discov, vol. 4, no. 8, Aug. 2014, pp. 896–904. Pubmed, doi:10.1158/2159-8290.CD-13-0230.
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. Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition. Cancer Discov. 2014 Aug;4(8):896–904.

Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

August 2014

Volume

4

Issue

8

Start / End Page

896 / 904

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Prostatic Neoplasms
  • Poly(ADP-ribose) Polymerases
  • Poly(ADP-ribose) Polymerase Inhibitors
  • PTEN Phosphohydrolase
  • Molecular Targeted Therapy
  • Mice
  • Male
  • Humans
  • Elafin