Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

    1. Luke A Selth1,2
    1. 1Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia
    2. 2Freemasons Foundation Centre for Men’s Health, School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia
    1. Correspondence should be addressed to L A Selth; Email: luke.selth{at}


    The androgen receptor (AR) signaling axis drives all stages of prostate cancer, including the lethal, drug-resistant form of the disease termed castration-resistant prostate cancer (CRPC), which arises after failure of androgen deprivation therapy (ADT). Persistent AR activity in spite of ADT and the second-generation AR-targeting agents enzalutamide and abiraterone is achieved in many cases by direct alterations to the AR signaling axis. Herein, we provide a detailed description of how such alterations contribute to the development and progression of CRPC. Aspects of this broad and ever-evolving field specifically addressed in this review include: the etiology and significance of increased AR expression; the frequency and role of gain-of-function mutations in the AR gene; the function of constitutively active, truncated forms of the AR termed AR variants and the clinical relevance of alterations to the activity and expression of AR coregulators. Additionally, we examine the novel therapeutic strategies to inhibit these classes of therapy resistance mechanisms, with an emphasis on emerging agents that act in a manner distinct from the current ligand-centric approaches. Throughout, we discuss how the central role of AR in prostate cancer and the constant evolution of the AR signaling axis during disease progression represent archetypes of two key concepts in oncology, oncogene addiction and therapy-mediated selection pressure.

    • Received 24 October 2016
    • Accepted 25 October 2016
    • Made available online as an Accepted Preprint 31 October 2016
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