Mechanisms of Androgen-Independent Prostate Cancer

Abstract

Prostate cancer is the second leading cause of cancer-related deaths among men in North America. Almost all prostate cancers begin in an androgen-dependent state, so androgen deprivation therapy is administered and results in improved clinical outcomes. However, over time, some cancerous cells are able to survive and grow during this treatment, resulting in androgen-independent prostate cancer. At this point, the disease is fatal, as there are no effective targeted therapies available. Most prostate cancer tumors require androgen receptor (AR) signalling for survival. During the progression to androgen-independence, this signalling cascade has been found to be altered at many levels within prostate cancers. Mechanisms that enhance AR signalling during androgen deprivation include: AR gene amplifications, AR gene mutations, changes in expression of AR co-regulatory proteins, changes in expression of steroid-generating enzymes, ligand-independent activation of AR via 'outlaw' pathways, and AR-independent pathways that become activated, termed 'bypass' pathways. One or more of these aforementioned changes can lead to prostate cancer cells to gain androgen-independent properties. Understanding the molecular alterations that occur during this process will allow for improved therapeutic strategies to target key molecules and pathways important for this progression.

Keywords: Androgen receptor; Androgen-independence; Androgen-independent prostate cancer; Castration-resistant prostate cancer; Prostate cancer; Prostate cancer progression.

Figure 1.

Prostate cancer diagnosis and treatment. After an initial physical digital rectal examination followed by a positive PSA test, a prostatic biopsy is examined. Based on histology, the biopsy will either confirm no cancer or cancer, and based on the Gleason scoring system, prostatic cancerous cells will be assessed a Gleason score. Gleason score 6 and less cancers do not require any curative treatments and undergo active surveillance, whereas Gleason 7 or higher cancers are normally treated with radical prostatectomy and androgen deprivation therapy. Patients often regress to androgen-independent prostate cancer, where there are no effective targeted therapies available.