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).

Low serum testosterone is associated with tumor aggressiveness and poor prognosis in prostate cancer

“…Previous human studies identified that patients with metastatic PCa with low serum testosterone levels had a worse response to endocrine therapy compared with patients with high serum testosterone levels (33,38). Notably, data from the present study is consistent with the general model of oncogene derepression as a mechanism of PCa progression (40). In this model, inhibition of AR function can lead to derepression of oncogenes that are normally repressed by the fully functional AR, leading to PCa progression.…”

Hybrid Enzalutamide Derivatives with Histone Deacetylase Inhibitor Activity Decrease Heat Shock Protein 90 and Androgen Receptor Levels and Inhibit Viability in Enzalutamide-Resistant C4-2 Prostate Cancer Cells

“…PCa is initially managed with surgery, radiation, androgen antagonists (e.g., bicalutamide), and surgical or chemical castration. However, relapsed or metastatic disease after castration [castration-recurrent prostate cancer (CRPC)] has a poor prognosis, with most patients dying within 2 years (Karantanos et al, 2015). Innovative approaches are urgently needed to treat patients with CRPC.…”

Experience with abiraterone acetate in the treatment of metastatic prostate cancer

“…При этом существуют подтвержденные данные, что около 60% больных с биохимическими рецидивами, резистентных к андрогенной депривации, отвечают на вторую линию гормональной терапии. Это отмечено при применении разных групп препаратов, блокирующих активацию ан-дрогенной оси [6][7][8]11]. Представлены результаты лечения 112 больных метастатическим кастратрезистентным раком предстательной железы (мкррПж) с использованием ингибитора биосинтеза андрогенов абиратерона ацетата во второй линии гормональной терапии.…”

“…При этом существуют подтвержденные данные, что около 60% больных с биохимическими рецидивами, резистентных к андрогенной депривации, отвечают на вторую линию гормональной терапии. Это отмечено при применении разных групп препаратов, блокирующих активацию ан-дрогенной оси [6][7][8]11]. Критичным ферментом в синтезе андрогенов являет-ся цитохром (CYP17A).…”