Canonical androgen receptor (AR) signaling regulates a network of DNA repair genes in prostate cancer (PCA). Experimental and clinical evidence indicates that androgen deprivation not only suppresses DNA repair activity but is often synthetically lethal in combination with PARP inhibition. The present study aimed to elucidate the impact of AR splice variants (AR-Vs), occurring in advanced or late-stage PCA, on DNA repair machinery.
Two hundred and seventy-three tissue samples were analyzed, including primary hormone-naïve PCA, primary metastases, hormone-sensitive PCA on androgen deprivation therapy (ADT) and castration refractory PCA (CRPC group). The transcript levels of the target genes were profiled using the nCounter platform. Experimental support for the findings was gained in AR/AR-V7-expressing LNCaP cells subjected to ionizing radiation.
AR-Vs were present in half of hormone-sensitive PCAs on androgen deprivation therapy (ADT) and two-thirds of CRPC samples. The presence of AR-Vs is highly correlated with increased activity in the AR pathway and DNA repair gene expression. In AR-V-expressing CRPC, the DNA repair score increased by 2.5-fold as compared to AR-V-negative samples. Enhanced DNA repair and the deregulation of DNA repair genes by AR-V7 supported the clinical data in a cell line model.
The expression of AR splice variants such as AR-V7 in PCA patients following ADT might be a reason for reduced or absent therapy effects in patients on additional PARP inhibition due to the modulation of DNA repair gene expression. Consequently, AR-Vs should be further studied as predictive biomarkers for therapy response in this setting.
Cancers. 2022 Sep 13*** epublish ***
Yuri Tolkach, Anika Kremer, Gábor Lotz, Matthias Schmid, Thomas Mayr, Sarah Förster, Stephan Garbe, Sana Hosni, Marcus V Cronauer, Ildikó Kocsmár, Éva Kocsmár, Péter Riesz, Abdullah Alajati, Manuel Ritter, Jörg Ellinger, Carsten-Henning Ohlmann, Glen Kristiansen
Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany., Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, 1085 Budapest, Hungary., Department of Medical Biometry, Informatics, and Epidemiology (IMBIE), University Hospital Bonn, 53127 Bonn, Germany., Department of Radiation Oncology, University Hospital Bonn, 53127 Bonn, Germany., Clinic of Urology, University Hospital Bonn, 53127 Bonn, Germany., Department of Urology, Semmelweis University, 1085 Budapest, Hungary., Department of Urology, Johanniter Krankenhaus Bonn, 53113 Bonn, Germany.