Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-017-00393-y
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Funding
- National Cancer Research Institute (National Institute of Health Research (NIHR) Collaborative Study: 'Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT) [G0500966/75466]
- Cancer Research UK
- Swedish Research Council
- AFA insurance
- Swedish Cancer Society
- Swedish Pain Relief Foundation
- Torsten and Ragnar Soderberg Foundation
- AstraZeneca Centre for Clinical Research (CKF)
- Vastmanland Research Foundation for Cancer in Vasteras
- Henning and Ida Persson Research Foundation
- Cancer Research UK [18796, 22310, 19556] Funding Source: researchfish
- National Institute for Health Research [ACF-2013-14-010] Funding Source: researchfish
- Public Health Agency [SPI/3315/06] Funding Source: researchfish
- Versus Arthritis
- Cancer Research UK [20406] Funding Source: researchfish
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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.
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