The Molecular Evolution of Castration-resistant Prostate Cancer.

CONTEXT: Androgen deprivation therapy (ADT) is the backbone of treatment for advanced prostate cancer. However, castration-resistant prostate cancer (CRPC) nearly invariably develops through a range of different molecular mechanisms accompanied by progression to a more aggressive phenotype.

OBJECTIVE: To understand the key molecular mechanisms leading to CRPC and the functional implications of this progression. Understanding molecular evolutionary mechanisms in CRPC is essential for the development of novel curative therapeutic approaches.

EVIDENCE ACQUISITION: A systematic literature search to identify relevant original articles was conducted using PubMed. Findings verified in independent studies and supported by in vivo data were prioritised. From the eligible collection, 50 papers were selected.

EVIDENCE SYNTHESIS: The majority of CRPC tumours harbour alterations in the androgen receptor (AR) at the DNA, RNA, and/or protein level, and/or other alterations involving the AR signalling pathway, so this central molecule is the focus of this review. To survive and resume growth despite low levels of circulating androgens, prostate cancer cells can also adapt androgen synthesis or induce alternative pathways.

CONCLUSIONS: Despite more efficient ADT strategies, most evidence points to persistent AR signalling as a major mechanism of progression to CRPC. Resistance due to transdifferentiation or AR independence is also emerging as a mechanism of resistance. The diversity of potential resistance mechanisms supports the need for combination treatment and serial monitoring for adaptive treatment strategies.

PATIENT SUMMARY: In this review, we summarise how prostate cancer cells evade androgen deprivation therapy and become more aggressive. Defining the molecular mechanisms will be critical for the development of new treatment approaches and hence improved survival.