Targeting the androgen receptor and overcoming resistance in prostate cancer

Abstract

Purpose of review: Prostate cancer (PCa) is diagnosed in one out of every nine men and is the second leading cause of cancer death among men. Although therapies targeting the androgen receptor (AR) are highly effective, development of resistance is universal and remains a major therapeutic challenge. Nonetheless, signaling via AR is frequently maintained despite standard androgen-signaling inhibition. We review the current understanding of mechanisms of resistance as well as therapeutic approaches to improving treatment of PCa via targeting of the AR.

Recent findings: Resistance to AR-targeting therapies may be mediated by several mechanisms, including amplification, mutation, and alternative splicing of AR; intratumoral androgen synthesis; activation of alternative signaling pathways; and in a minority of cases, emergence of AR-independent phenotypes. Recent trials demonstrate that intensification of androgen blockade in metastatic castration-sensitive PCa can significantly improve survival. Similar strategies are being explored in earlier disease states. In addition, several other cellular signaling pathways have been identified as mechanisms of resistance, offering opportunities for cotargeted therapy. Finally, immune-based approaches are in development to complement AR-targeted therapies.

Summary: Targeting the AR remains a critical focus in the treatment of PCa.

Figure 1.. Landscape of AR activity, RB1/TP53 activity, and neuroendocrine features in advanced PCa.

Each dot reflects hypothetical level of AR activity, RB1/TP53 activity, and neuroendocrine differentiation in an individual advanced tumor that is resistant to AR targeted therapies.

Figure 2.

Standard and experimental approaches to target AR across the spectrum of PCa.