Leading causes of castration-resistant prostate cancer

Abstract

Prostate cancer (PCa) is the second leading cause of cancer-related death in men. Androgen receptor has a key role in the initiation and progression of PCa. Currently, androgen deprivation therapy is the standard treatment for PCa patients due to its effective suppression of androgen receptor signaling. Even though androgen deprivation therapy shows its initial effectiveness on shrinking tumor size, it eventually fails to cure advanced PCa, which is determined by the occurrence of castration-resistance. In this review, we summarize the widely accepted mechanisms that account for castration-resistant PCa and discuss potential therapeutic targets.

Keywords:

• androgen receptor
• androgen receptor mutation
• androgen receptor splicing
• castration-resistant prostate cancer
• neuroendocrine
• progenitor cells

Financial & competing interests disclosure

This work is supported by science foundation of Educational Commission of Hubei Province of China (D20141205) and science foundation of Yichang (A12301-03). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Although androgen deprivation therapy plus anti-androgen show promising efficacy, it eventually conveys drug resistance to prostate cancer patients.

• Androgen receptors (AR) mutants and AR variants are caused by anti-androgens. EP001 and ASC-J9 are potential clinical drugs to target AR regardless of its status.

• AR gene amplification is another contributor, which amplifies AR sensitivity in the stage of castration-resistant prostate cancer.

• Increased population of prostate cancer stem cells and elevated NE differentiation are both correlated with anti-androgen treatment.

• Reactivation of AR signaling by glucocorticoid receptor upregulation renders enzalutamide resistance to prostate cancer.

• Non-AR signaling pathways such as PI3K/AKT/mTOR are implicated in the development of castration-resistant prostate cancer.