DNA Damage Repair Deficiency in Prostate Cancer

A significant proportion of prostate cancers harbor DNA damage repair (DDR) deficiency. These are particularly encountered in aggressive high-grade carcinoma and advanced metastatic disease. AR pathway signaling is frequently perturbed in prostate cancer and interacts with DDR pathway utilization. Functional defects in DDR pathways can sensitize tumors to genotoxic treatments, such as radiotherapy or chemotherapy. Molecular targeting of back-up DDR pathways can induce synthetic sensitivity or lethality in nonhomologous end-joining (NHEJ)/homologous recombination (HR)-deficient prostate tumors. Indicators of DDR defects may serve as predictive biomarkers for personalized treatment. Molecular-targeted therapies and treatment stratification based on molecular biomarkers have rapidly gained momentum in the therapeutic spectrum for patients with prostate cancer, particularly those with aggressive disease. DNA damage repair (DDR) pathways are commonly impaired in prostate cancer. Recent studies have detailed mechanisms interconnecting the DDR with the androgen receptor (AR) signaling pathway as well as its interplay with the immune response. The prominent role of DDR deficiency in prostate cancer development and treatment response encourages innovative strategies for the detection of DDR deficiency in individual tumors. In this review, we describe recent preclinical and early clinical data on the exploitation of DDR defects as predictive biomarkers and also as molecular therapeutic targets. Molecular-targeted therapies and treatment stratification based on molecular biomarkers have rapidly gained momentum in the therapeutic spectrum for patients with prostate cancer, particularly those with aggressive disease. DNA damage repair (DDR) pathways are commonly impaired in prostate cancer. Recent studies have detailed mechanisms interconnecting the DDR with the androgen receptor (AR) signaling pathway as well as its interplay with the immune response. The prominent role of DDR deficiency in prostate cancer development and treatment response encourages innovative strategies for the detection of DDR deficiency in individual tumors. In this review, we describe recent preclinical and early clinical data on the exploitation of DDR defects as predictive biomarkers and also as molecular therapeutic targets.