Drug Insight: role of the androgen receptor in the development and progression of prostate cancer

Abstract

Functional androgen receptor (AR) signaling is necessary for the development of prostate cancer. The therapeutic effect of androgen deprivation therapy for prostate cancer was described over 60 years ago and this treatment remains the mainstay of systemic therapy despite its transient response duration. It has become clear that AR expression and signaling remains intact as the disease evolves from androgen-sensitive cancer to classically (but perhaps inaccurately) termed hormone refractory prostate cancer. Through several genetic and epigenetic adaptations, prostate tumors continue to rely on AR growth signaling and they thus remain targets of 'hormonal' therapy. The development of new strategies and drugs that can abrogate AR signaling will probably result in important clinical benefits. The biology of androgen independence and the development of new approaches targeting AR signaling are reviewed herein.

Key Points

  • More-effective 'hormone therapy' is needed for prostate cancer

  • Despite the development of classically termed 'hormone refractory' prostate cancer, androgen receptor signaling remains an active growth-promoting pathway

  • The androgen receptor remains an important therapeutic target in hormone refractory prostate cancer

  • As prostate tumors develop in castrated men, AR signaling is maintained through AR amplification and mutation and the 'intracrine' production of androgen

  • Novel approaches to androgen receptor inhibition are in development and include more-potent antiandrogens, lyase inhibitors, 5α-reductase inhibitors, HSP90 inhibitors, and HDAC inhibitors

  • More-effective 'hormone therapy' might be achieved through combined inhibition of classic androgen receptor signaling and other interrelated pathways such as mTOR, EGFR or MAPK

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Figure 1: Androgen receptor structure and function

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Taplin, M. Drug Insight: role of the androgen receptor in the development and progression of prostate cancer. Nat Rev Clin Oncol 4, 236–244 (2007). https://doi.org/10.1038/ncponc0765

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