Activation of the androgen receptor (AR) and AR-driven transcriptional programs is central to the pathophysiology of prostate cancer. Despite successful translational efforts in targeting AR, therapeutic resistance often occurs as a result of molecular alterations in the androgen signaling axis. The efficacy of next-generation AR-directed therapies for castration-resistant prostate cancer has provided crucial clinical validation for the continued dependence on AR signaling and introduced a range of new treatment options for men with both castration-resistant and castration-sensitive disease. Despite this, however, metastatic prostate cancer largely remains an incurable disease, highlighting the need to better understand the diverse mechanisms by which tumors thwart AR-directed therapies, which may inform new therapeutic avenues. In this review, we revisit concepts in AR signaling and current understandings of AR signaling-dependent resistance mechanisms as well as the next frontier of AR targeting in prostate cancer.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2023 Jul 10 [Epub ahead of print]
Charles Dai, Scott M Dehm, Nima Sharifi
Massachusetts General Hospital Cancer Center, Boston, MA., Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN., Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.