Background Clinical and preclinical studies have revealed that alterations in DNA damage response (DDR) pathways may play an important role in prostate cancer (PCa) etiology and progression. These alterations can influence PCa responses to radiotherapy and anti-androgen treatment. The identification of DNA repair gene aberrations in PCa has driven the interest for further evaluation whether these genetic changes may serve as biomarkers for patient stratification. Methods In this review, we summarize the current knowledge on DDR alterations in PCa, their potential impact on clinical interventions and prospects for improved management of PCa. We particularly focus on the influence of DDR gene mutations on PCa initiation and progression and describe the underlying mechanisms. Results and Conclusions A better understanding of these mechanisms, will contribute to better disease management as treatment strategies can be chosen based on the specific disease properties, since a growing number of treatments are targeting DDR pathway alterations (such as Poly(ADP-ribose) polymerase inhibitors). Furthermore, the recently discovered crosstalk between the DDR and androgen receptor signaling opens a new array of possible strategies to optimize treatment combinations. We discuss how these recent and ongoing studies will help to improve diagnostic, prognostic and therapeutic approaches for PCa management.

Background In vitro models of prostate cancer (PCa) are not always reliable to evaluate anticancer treatment efficacy. This limitation may be overcome by using viable tumor slice material. Here we report on the establishment of an optimized ex vivo method to culture tissue slices from patient‐derived xenografts (PDX) of prostate cancer (PCa), to assess responses to PCa treatments. Methods Three PDX models were used that are characterized by different androgen receptor (AR) expression and different homology directed DNA repair capacities, due to a breast cancer associated two ( BRCA2 ) wild‐type or mutated status. Tumors were removed from mice, sliced using a vibratome and cultured for a maximum of 6 days. To test the sensitivity to androgen antagonist, tumor slices from the AR‐expressing and AR‐negative PDX tumors were treated with the anti‐androgen enzalutamide. For sensitivity to DNA repair intervention, tumors slices from BRCA2 wild‐type and mutated PDXs were treated with the poly (ADP‐ribose) polymerase‐1 inhibitor olaparib. Treatment response in these tumor slices was determined by measuring slice morphology, cell proliferation, apoptosis, AR expression level, and secretion of prostate specific antigen (PSA). Results We compared various culture conditions (support materials, growth media, and use of a 3D smooth rocking platform) to define the optimal condition to maintain tissue viability and proliferative capacity up to least 6 days. Under optimized conditions, enzalutamide treatment significantly decreased proliferation, increased apoptosis, and reduced AR‐expression and PSA secretion of AR‐expressing tumor slices compared to AR‐negative slices, that did not respond to the intervention. Olaparib treatment significantly increased cell death in BRCA2 mutated tumors slices as compared to slices from BRCA2 wild type tumors. Conclusions Ex vivo treatment of PCa PDX tumor slices with enzalutamide and olaparib recapitulates responses previously observed in vivo. The faithful retention of tissue structure and function in this ex vivo model offers an ideal opportunity for treatment efficacy screening, thereby reducing costs and numbers of experimental animals.

Androgen-deprivation therapy was shown to improve treatment outcome of external beam radiation therapy (EBRT) for locally advanced prostate cancer (PCa). DNA damage response (DDR) was suggested to play a role in the underlying mechanism, but conflicting results were reported. This study aims to reveal the role of the androgen receptor (AR) in EBRT-induced DDR and to investigate whether next-generation AR inhibitor apalutamide can radiosensitize PCa. PCa cell lines and tissue slices were treated with anti-androgen alone or combined with EBRT. The effect of treatments on cell growth, tissue viability, DDR, and cell cycle were investigated. RAD51 and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) levels were determined by Western blotting. Homologous recombination (HR) capacity was measured with the directed repeats-green fluorescent protein (DR-GFP) assay. We report the radiosensitizing effect of anti-androgens, which showed synergism in combination with EBRT in AR-expressing tumor slices and cell lines. Moreover, a compromised DDR was observed in AR-expressing cells upon AR suppression. We found that AR inhibition downregulated DNA-PKcs expression, resulting in reduced non-homologous end-joining repair. DDR through HR was a secondary effect due to cell-cycle change. These data provide a mechanistic explanation for the combination regimen and support the clinical use of apalutamide together with EBRT for localized PCa patients.