Androgen receptor and DNA damage response crosstalk: Mechanisms and impact on cancer progression

Prostate cancer (PCa) is the most frequently diagnosed non-cutaneous malignancy and the second leading cause of cancer-related death amongst men living in the United States. While localized disease can be effectively treated/managed through radical prostatectomy and/or radiation therapy, treatment of disseminated PCa represents a significant clinical challenge. As studies have determined that PCa development and progression is driven by androgen receptor (a ligand dependent nuclear receptor) activity at all stages of disease, targeted inhibition of this pathway, usually through systemic hormonal therapy or direct AR antagonism, is the first-line and most effective therapeutic option for treatment of advanced and metastatic disease. While these treatments are initially effective, tumors resistant to AR-directed therapies ultimately arise through a variety of mechanisms, with no durable treatment options available at this stage. Thus, significant efforts have been directed at characterizing the collective networks that impinge upon the AR signaling axis and drive therapeutic resistance and subsequent progression to advanced stages of disease. Work herein will describe mechanisms of cross talk between AR and the DNA damage response (DDR) that promote therapeutic resistance and advanced tumor phenotypes in PCa and characterize a transcriptional regulatory role for the DDR factor DNA-dependent protein kinase catalytic subunit (DNA-PKcs) that drives PCa progression and metastatic development. Collectively, these studies utilized models encompassing in vitro (cell lines), in vivo (subcutaneous xenografts and metastatic development), and ex vivo (primary human tumor explants) systems. Techniques encompassing biochemistry, pharmacology, molecular biology, genetics, histology, and pathology were utilized to investigate hypotheses. Based on the data collected, it will be concluded that crosstalk between AR and the DDR results in a positive feedback circuit contributing to proliferation and therapeutic resistance, and that one AR-regulated DDR factor, DNA-PKcs, is a key transcriptional modulator of gene networks that drive disease progression and metastatic formation and a clinical predictor of development of metastases and poor outcome. Combined, these findings identify novel therapeutic options for treatment of advanced PCa