Abstract
In the past decades, the field of prostate cancer (PCa) biology has developed exponentially and paralleled with that has been the growing interest in translation of laboratory findings into clinical practice. Based on overwhelming evidence of high impact research findings which support the underlying cause of insufficient drug efficacy in patients progressing on standard androgen deprivation therapy (ADT) is due to persistent activation of the androgen receptor (AR) signaling axis. Therefore, newer agents must be discovered especially because newer ADT such as abiraterone and enzalutamide are becoming ineffective due to rapid development of resistance to these agents. High-throughput technologies are generating massive and highly dimensional genetic variation data that has helped in developing a better understanding of the dynamic repertoire of AR and AR variants. Full length AR protein and its variants modulate a sophisticated regulatory system to orchestrate cellular responses. We partition this multicomponent review into subsections addressing the underlying mechanisms of resistance to recent therapeutics, positive and negative regulators of AR signaling cascade, and how SUMOylation modulates AR induced transcriptional activity. Experimentally verified findings obtained from cell culture and preclinical studies focusing on the potential of natural agents in inhibiting mRNA/protein levels of AR, nuclear accumulation and enhanced nuclear export of AR are also discussed. We also provide spotlight on molecular basis of enzalutamide resistance with an overview of the strategies opted to overcome such resistance. AR variants are comprehensively described and different mechanisms that regulate AR variant expression are also discussed. Reconceptualization of phenotype- and genotype-driven studies have convincingly revealed that drug induced resistance is a major stumbling block in standardization of therapy. Therefore, we summarize succinctly the knowledge of drug resistance especially to ADT and potential avenues to overcome such resistance for improving the treatment outcome of PCa patients.
Highlights
Androgen receptor (AR) blockers have been incorporated in the backbone of prostate cancer (PCa) therapeutics
First generation AR antagonists such as bicalutamide and nilutamide gained appreciation but agonistic properties were noted in AR over-expressing PCa cells, which raised some concerns for the use of these agents in human PCa patients
Benzodiazepine-based inhibitors and 2-(4-Chlorophenyl)-2-oxoethyl 4-benzamidobenzoate derivatives have shown potential in targeting of SENP1 [21,22] (Figure 2). These recent reports suggest that newer arsenals are beginning to emerge for AR-targeted therapeutics which could be useful in improving the therapeutic outcome of PCa patients especially for patients with castration resistant prostate cancer (CRPC) and/ or mCRPC
Summary
Androgen receptor (AR) blockers have been incorporated in the backbone of PCa therapeutics. There are encouraging advancements in our understanding related to the intricacies that mediate androgen metabolism and thereby regulate AR activation [4], we still need in-depth analysis and identification of agents perhaps natural agents (no known toxicity in human) that can overcome resistance against current and next-generation AR targeting agents. Positive and negative regulators of AR and AR induced signaling Substantial information has been added into the landscape of co-activator/co-repressor complexes associated with AR (Figure 1), and it is known that AR interacted with phosphorylated heterogeneous nuclear ribonucleoprotein K (hnRNP K) in nuclear matrix region in PCa cells. Targeted inhibition of MID1 in AR overexpressing DuCaP cells notably reduced decreased protein levels of AR [8]. Jumonji domain-containing demethylase, KDM4C is a well known protein reported to enhance AR mediated transcriptional activity by modulating H3K9 demethylation. SD70 treated PCa cells and displayed a marked decrease in AR target gene expression [12,13]
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