Abstract
Simple SummaryApproximately 1 in 8 men will be diagnosed with prostate cancer (PCa) at some point in their lifetime. Five-year survival rate for patients with local or regionally spread disease is near 100%, but this drops to 30% when the cancer has spread to distant sites. Androgen receptor (AR) signaling plays a pivotal role in normal prostate development and PCa cell survival. Therapies targeting the AR pathway are mainline treatments, but resistance is a major clinical problem. From the literature and our own meta-analysis of PCa databases, we aimed to review the connections between PCa genetic alterations and the AR signaling axis at the primary stage. Assessing how combinations of PCa genetic drivers that arise in patients affect AR signaling will aid in stratifying patients who will likely respond to AR-directed therapies, and those who will require other therapeutic agents upfront in order to prevent disease progression.While many prostate cancer (PCa) cases remain indolent and treatable, others are aggressive and progress to the metastatic stage where there are limited curative therapies. Androgen receptor (AR) signaling remains an important pathway for proliferative and survival programs in PCa, making disruption of AR signaling a viable therapy option. However, most patients develop resistance to AR-targeted therapies or inherently never respond. The field has turned to PCa genomics to aid in stratifying high risk patients, and to better understand the mechanisms driving aggressive PCa and therapy resistance. While alterations to the AR gene itself occur at later stages, genomic changes at the primary stage can affect the AR axis and impact response to AR-directed therapies. Here, we review common genomic alterations in primary PCa and their influence on AR function and activity. Through a meta-analysis of multiple independent primary PCa databases, we also identified subtypes of significantly co-occurring alterations and examined their combinatorial effects on the AR axis. Further, we discussed the subsequent implications for response to AR-targeted therapies and other treatments. We identified multiple primary PCa genomic subtypes, and given their differing effects on AR activity, patient tumor genetics may be an important stratifying factor for AR therapy resistance.
Highlights
Prostate cancer (PCa), the most commonly diagnosed cancer in men in the United States, remains the second leading cause of U.S male cancer related deaths
In PCa cell lines, inhibition of p53 or TP53 overexpression both decreased androgen receptor (AR)-mediated signaling, and TP53 loss of function was sufficient to decrease AR protein expression [81]. These results suggest that a tight balance in p53 and AR levels is important for normal AR function, and that disruption to this may contribute to disease progression
We have identified five genomic subtypes of primary PCa that each involve at least two significantly co-occurring alterations: MAP3K7/CHD1/SPOP; ERG/PTEN/TP53; ATM/PARP1; BRCA1/TP53; BRCA2/RB1
Summary
Prostate cancer (PCa), the most commonly diagnosed cancer in men in the United States, remains the second leading cause of U.S male cancer related deaths. The AR signaling axis is a critical dependence for many early and late stage PCa tumors, making AR-directed therapies a front-line treatment for local and metastatic disease [4,5,6]. These therapies include two general mechanisms of action: Depleting androgen hormone levels, known as androgen deprivation therapy [7], and directly inhibiting AR function using antiandrogens, such as enzalutamide. We will review what is known about the relation of these genomic subtypes to AR-targeted therapy response and other therapies that have preclinical indications for specific alterations
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