Prostate cancer (PCa) is the most frequently diagnosed cancer in the United States. The androgen receptor (AR) signaling axis is central to all stages of PCa pathophysiology and serves as the main target for endocrine-based therapy. The most advanced stage of the disease, castration-resistant prostate cancer (CRPC), is presently incurable and accounts for most PCa mortality. In this chapter, we highlight the mechanisms by which the AR signaling axis can bypass endocrine-targeted therapies and drive progression of CRPC. These mechanisms include alterations in growth factor, cytokine, and inflammatory signaling pathways, altered expression or activity of transcriptional coregulators, AR point mutations, and AR gene amplification leading to AR protein overexpression. Additionally, we will discuss the mechanisms underlying the synthesis of constitutively active AR splice variants (AR-Vs) lacking the COOH-terminal ligand-binding domain, as well as the role and regulation of AR-Vs in supporting therapeutic resistance in CRPC. Finally, we summarize the ongoing development of inhibitors targeting discrete AR functional domains as well as the status of new biomarkers for monitoring the AR signaling axis in patients.
|Original language||English (US)|
|Title of host publication||Advances in Pharmacology|
|Publisher||Academic Press Inc.|
|Number of pages||40|
|State||Published - 2014|
|Name||Advances in Pharmacology|
Bibliographical noteFunding Information:
Studies in the Dehm Lab have been supported by the Grants from the National Institutes of Health (R01 CA174777 to S. M. D.), an American Cancer Society Research Scholar Grant (RSG-12-031-01 to S. M. D.), and a Department of Defense Prostate Cancer Research Program New Investigator Award (W81XWH-10-1-0353 to S. M. D.). S. M. D. is a masonic scholar of the Masonic Cancer Center, University of Minnesota.
- Androgen receptor
- Castration-resistant prostate cancer
- Constitutive activity
- Prostate cancer
- Splice variant