Overview on the complexity of androgen receptor-targeted therapy for prostate cancer

Cancer Cell International

Fazlul H Sarkar²  Ammad Ahmad Farooqi¹ 

[1] Laboratory for Translational Oncology and Personalized Medicine, Rashid Latif Medical College, 35 Km Ferozepur Road, Lahore, Pakistan;Departments of Pathology and Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 740 HWCRC, 4100 JohnR Street, Detroit 48201, MI, USA

关键词: Apoptosis;    Intracellular signaling;    Prostate cancer;   

Others  :  1138649
DOI  :  10.1186/s12935-014-0153-1

 received in 2014-10-23, accepted in 2014-12-23,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Farooqi and Sarkar; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

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