Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer.
Asim M., Tarish F., Zecchini HI., Sanjiv K., Gelali E., Massie CE., Baridi A., Warren AY., Zhao W., Ogris C., McDuffus L-A., Mascalchi P., Shaw G., Dev H., Wadhwa K., Wijnhoven P., Forment JV., Lyons SR., Lynch AG., O'Neill C., Zecchini VR., Rennie PS., Baniahmad A., Tavaré S., Mills IG., Galanty Y., Crosetto N., Schultz N., Neal D., Helleday T.
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.Tumours with homologous recombination (HR) defects become sensitive to PARPi. Here, the authors show that androgen receptor (AR) regulates HR and AR inhibition activates the PARP pathway in vivo, thus inhibition of both AR and PARP is required for effective treatment of high risk prostate cancer.