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Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer.

Authors :
Asim, Mohammad
Tarish, Firas
Zecchini, Heather I.
Sanjiv, Kumar
Gelali, Eleni
Massie, Charles E.
Baridi, Ajoeb
Warren, Anne Y.
Wanfeng Zhao
Ogris, Christoph
McDuffus, Leigh-Anne
Mascalchi, Patrice
Shaw, Greg
Dev, Harveer
Wadhwa, Karan
Wijnhoven, Paul
Forment, Josep V.
Lyons, Scott R.
Lynch, Andy G.
O’Neill, Cormac
Source :
Nature Communications; 8/29/2017, Vol. 8 Issue 1, p1-10, 10p, 4 Graphs
Publication Year :
2017

Abstract

Emerging data demonstrate homologous recombination (HR) defects in castration-resistant prostate cancers, rendering these tumours sensitive to PARP inhibition. Here we demonstrate a direct requirement for the androgen receptor (AR) to maintain HR gene expression and HR activity in prostate cancer. We show that PARP-mediated repair pathways are upregulated in prostate cancer following androgen-deprivation therapy (ADT). Furthermore, upregulation of PARP activity is essential for the survival of prostate cancer cells and we demonstrate a synthetic lethality between ADT and PARP inhibition in vivo. Our data suggest that ADT can functionally impair HR prior to the development of castration resistance and that, this potentially could be exploited therapeutically using PARP inhibitors in combination with androgen-deprivation therapy upfront in advanced or high-risk prostate cancer. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
20411723
Volume :
8
Issue :
1
Database :
Complementary Index
Journal :
Nature Communications
Publication Type :
Academic Journal
Accession number :
139686564
Full Text :
https://doi.org/10.1038/s41467-017-00393-y