Understanding the Mechanisms of Androgen Deprivation Resistance in Prostate Cancer at the Molecular Level

Abstract

Context To evaluate molecular mechanisms that play a role in the development of resistance to androgen deprivation therapy in castration-resistant prostate cancer. Objective The understanding of mechanisms and biological pathways associated with the progression of prostate cancer under systemic androgen depletion or administration of novel anti-androgens abiraterone, enzalutamide and ARN-509. This review also examines the introduction of novel combinational approaches for patients with castrate resistant prostate cancer. Evidence Acquisition Pubmed was the data source and “castrate resistant prostate cancer”, “abiraterone, enzalutamide resistance mechanisms”, “resistance to androgen deprivation”, “AR mutations”, “amplifications”, “splice variants” and “AR alterations” were the keywords for the search. Papers published before 1990 were excluded from the review and only English papers were included. Evidence Synthesis This review summarizes the current literature regarding the mechanisms implicated in the development of castrate resistant prostate cancer and the acquisition of resistance to novel anti-androgen axis agents. It focuses on androgen biosynthesis in the tumor microenvironment, AR alterations and post-transcriptional modifications, the role of glucocorticoid receptor, pathways of cellular stress and alternative oncogenic signaling which are de-repressed upon maximum AR inhibition promoting cancer survival and progression. Conclusions The mechanisms implicated in the development of resistance to AR inhibition in prostate cancer are multiple and complex, involving virtually all classes of genomic alteration and leading to a host of selective/adaptive responses . Combinational therapeutic approaches targeting both AR signaling and alternative oncogenic pathways may be reasonable for patients with castrate resistant prostate cancer. Patient Summary In this review we looked for mechanisms related to the progression of prostate cancer in patients undergoing hormonal therapy and treatment with novel drugs targeting the androgen receptor. Based on recent data, the combination of maximal androgen receptor inhibition with novel agents targeting other tumor compensatory, non-AR related pathways may improve the survival and quality of life of patients with castrate-resistant prostate cancer (CRPC).