title: Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence.
abstract: 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.
authors: Dame Roma Mitchell Cancer Research LaboratoriesSchool of Medicine, The University of Adelaide, Adelaide, South Australia, Australia.|Freemasons Foundation Centre for Men's HealthSchool of Medicine, The University of Adelaide, Adelaide, South Australia, Australia.
authors: Isabel
authors: I
authors: Coutinho
authors: Dame Roma Mitchell Cancer Research LaboratoriesSchool of Medicine, The University of Adelaide, Adelaide, South Australia, Australia.|Freemasons Foundation Centre for Men's HealthSchool of Medicine, The University of Adelaide, Adelaide, South Australia, Australia.
authors: Tanya K
authors: TK
authors: Day
authors: Dame Roma Mitchell Cancer Research LaboratoriesSchool of Medicine, The University of Adelaide, Adelaide, South Australia, Australia.|Freemasons Foundation Centre for Men's HealthSchool of Medicine, The University of Adelaide, Adelaide, South Australia, Australia.
authors: Wayne D
authors: WD
authors: Tilley
authors: Dame Roma Mitchell Cancer Research LaboratoriesSchool of Medicine, The University of Adelaide, Adelaide, South Australia, Australia luke.selth@adelaide.edu.au.|Freemasons Foundation Centre for Men's HealthSchool of Medicine, The University of Adelaide, Adelaide, South Australia, Australia.
authors: Luke A
authors: LA
authors: Selth
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy / Q000379:methods / Q000639:trends; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D011944:Receptors, Androgen
keywords: androgen receptor; endocrine therapy resistance; hormone structure/function; prostate