Prostate cancer (PCa) is the most common form of cancer for men in the developed world and the second leading cause of cancer-related deaths. While advanced PCa is initially controlled with hormonal therapies targeting the androgen receptor (AR) pathway, recurrence occurs due to the emergence of lethal castration-resistant PCa (CRPC). Despite newer AR pathway inhibitors that prolong survival, resistance still emerges, most often with rising PSA indicative of AR-driven activity, but increasingly as non-AR-driven cancer. Treatment resistance mechanisms include androgen receptor (AR)-signaling pathway alterations, AR-signaling bypass mechanisms, and AR-independent clonal evolution. The latter mechanism can lead to the emergence of neuroendocrine prostate cancer (NEPC), an aggressive lethal subtype of PCa. The incidence of treatment-induced NEPC is rising due to the widespread use of more potent AR pathway inhibitors. This comprehensive review of major NEPC drivers and facilitators define three coordinated processes contributing to NEPC progression. Specifically, castration-resistant adenocarcinoma (AdPC) cells gain lineage plasticity under selective pressures of potent AR suppression to transform into AR-independent tumor cells. In concert, neuroendocrine-specific transdifferentiation factors induce neuroendocrine lineage of these PCa cells, which with support of increased proliferation factors, contributes to clonal expansion and tumor repopulation into NEPC. We examine the roles of each of the major NEPC contributors during the disease progression and identify potential therapeutic opportunities for targeted therapies. This article is protected by copyright. All rights reserved.
BJU international. 2018 Mar 22 [Epub ahead of print]
Ruiqi Chen, Xuesen Dong, Martin Gleave
Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Canada.