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Medical Oncology

, 33:44 | Cite as

Targeting persistent androgen receptor signaling in castration-resistant prostate cancer

  • Laura Graham
  • Michael T. Schweizer
Review Paper

Abstract

Castration-resistant prostate cancer (CRPC), the invariably lethal phenotype of advanced prostate cancer, represents a clinical state defined by disease progression despite reduction of testosterone to castrate levels (i.e., ≤50 ng/dL). Although resistant to androgen-deprivation therapy (i.e., LHRH agonists/antagonists), CRPC continues to depend on the androgen receptor (AR)-signaling pathway. Supporting the importance of AR-signaling in a castration-resistant state, the next-generation AR-signaling inhibitors enzalutamide and abiraterone have been shown to afford a survival benefit in men with metastatic CRPC. However, primary and secondary resistance mechanisms to these agents inevitably drive continued disease progression—often as a result of re-activation of AR-signaling. With increased understanding of the mechanisms underlying how continued AR-signaling occurs in spite of drugs like abiraterone and enzalutamide, a new wave of therapies is emerging designed to more effectively target AR-signaling. This review will focus on the more clinically relevant mechanisms of CRPC drug resistance and our ongoing efforts to develop drugs to target these mechanisms.

Keywords

Castration-resistant prostate cancer Androgen receptor Androgen receptor splice variant Hormonal therapy Androgen-deprivation therapy Enzalutamide Abiraterone Drug resistance 

Notes

Compliance with ethical standards

Conflict of interest

None.

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of MedicineUniversity of WashingtonSeattleUSA
  2. 2.Division of Oncology, Department of MedicineUniversity of Washington/Fred Hutchinson Cancer Research CenterSeattleUSA

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