Targeting the androgen receptor and overcoming resistance in prostate cancer

被引:32
|
作者
Einstein, David J. [1 ]
Arai, Seiji [1 ]
Balk, Steven P. [1 ]
机构
[1] Beth Israel Deaconess Med Ctr, Div Med Oncol, Boston, MA 02215 USA
关键词
androgen receptor; androgen-signaling inhibitors; castration resistance; prostate cancer; GLUCOCORTICOID-RECEPTOR; ABIRATERONE ACETATE; NEUROENDOCRINE PHENOTYPE; DEPRIVATION THERAPY; LINEAGE PLASTICITY; SMALL-MOLECULES; ASSOCIATION; VARIANTS; MEN; ENZALUTAMIDE;
D O I
10.1097/CCO.0000000000000520
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:175 / 182
页数:8
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