Development and prevalence of castration-resistant prostate cancer subtypes

Abstract

Background Castration-resistant prostate cancer (CRPC) occurs when prostate cancer (CaP) progresses under therapy-induced castrate conditions. Several mechanisms have been proposed to explain this acquired resistance, many of which are driven by androgen receptor (AR). Recent findings, however, sub-classified CRPC by downregulation/absence of AR in certain subtypes that consequently do not respond to anti-androgen therapies. To highlight the significance of CRPC sub-classification, we reviewed the development and treatment of CRPC, AR downregulation in CRPC, and summarized recent reports on the prevalence of CRPC subtypes. Methods Using a medline-based literature search, we reviewed mechanisms of CRPC development, current treatment schemes, and assessed the prevalence of AR low/negative subtypes of CRPC. Additionally, we performed immunohistochemical staining on human CRPC specimens to quantify AR expression across CRPC subtypes. Results In the majority of cases, CRPC continues to rely on AR signaling, which can be augmented in castrate-conditions through a variety of mechanisms. However, recently low/negative AR expression patterns were identified in a significant proportion of patient samples from a multitude of independent studies. In these AR low/negative cases, we postulated that AR protein may be downregulated by (1) promoter methylation, (2) transcriptional regulation, (3) post-transcriptional regulation by microRNA or RNA-binding-proteins, or (4) post-translational ubiquitination-mediated degradation. Conclusions Here, we discussed mechanisms of CRPC development and summarized the overall prevalence of CRPC subtypes; interestingly, AR low/negative CRPC represented a considerable proportion of diagnoses. Because these subtypes cannot be effectively treated with AR-targeted therapeutics, a better understanding of AR low/negative subtypes could lead to better treatment strategies and increased survival.

Undesirable Status of Prostate Cancer Cells after Intensive Inhibition of AR Signaling: Post-AR Era of CRPC Treatment

“…Interestingly, in the era before the approval of ARSTAs, including abiraterone acetate and enzalutamide, most CRPC were AR-dependent PC (88.4%) with rare NEPC (6.3%) and DNPC (5.4%), although tumor phenotypic changes with a higher percentage of DNPC (23.3%) were observed in the contemporary era [ 1 ]. Thus, potent suppression of AR signaling promotes the development of a variety of castration-resistant tumor subtypes, ranging from tumors that remain positive for AR-dependent PC and NEPC to DNPC [ 131 ].…”

Non-Coding RNAs Set a New Phenotypic Frontier in Prostate Cancer Metastasis and Resistance

“…NEPC is poorly differentiated, progresses rapidly, and metastases to visceral organs [ 73 ], with a median patient survival of 7 months [ 72 ]. It is characterized by the absence of AR [ 74 ] and the expression of neuroendocrine markers such as synaptophysin (SYP), chromogranin A (CHGA) and enolase 2 (ENO2) [ 73 , 74 ]. While NEPC rarely arises de novo and accounts for less than 2% of all primary prostate cancer diagnoses [ 71 ], therapy-induced NEPC (t-NEPC) can develop from divergent clonal evolution from CRPC in response to the selective pressure of ADT [ 72 , 73 ] and has a much higher incidence, ranging from 17–30% [ 73 ].…”

Recent developments and applications of quantitative proteomics strategies for high-throughput biomolecular analyses in cancer research

“…44 Further analyses of the literature have characterized these CRPC subtypes and demonstrated the growing emergence of CRPC phenotypes that have either low or negative AR expression for which there are few targeted therapeutics. 45 The growing heterogeneity in prostate cancer subtype underscores the urgency to elucidate and discover novel molecular mechanisms underlying pathogenesis for all subtypes. The use of mass spectrometry (MS)based quantitative proteomics for prostate cancer research in recent years has been a driving force to exploit the factors underlying tumorigenesis and metastasis.…”