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Novel Insights into Molecular Indicators of Response and Resistance to Modern Androgen-Axis Therapies in Prostate Cancer

  • Prostate Cancer (A Kibel, Section Editor)
  • Published:
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Abstract

While androgen ablation remains a mainstay for advanced prostate cancer therapy, nearly all patients will inevitably develop disease escape with time. Upon the development of castration-resistant prostate cancer, other androgen-axis-targeted treatments may be added in an effort to starve the disease of its androgen signaling. Nevertheless, additional androgen-pathway resistance usually develops to these novel hormonal therapies. In this review, we will discuss the resistance mechanisms to modern androgen-axis modulators and how these alterations can influence a patient’s response to novel hormonal therapy. We conceptualize these resistance pathways as three broad categories: (1) reactivation of androgen/AR-signaling, (2) AR bypass pathways, and (3) androgen/AR-independent mechanisms. We highlight examples of each, as well as potential therapeutic approaches to overcome these resistance mechanisms.

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Abbreviations

ADT:

androgen deprivation therapy

AR:

androgen receptor

ARE:

androgen response element

AR-FL:

full-length androgen receptor

AR-V:

androgen receptor splice variant

cfDNA:

cell-free DNA

CRPC:

castration-resistant prostate cancer

CTC:

circulating tumor cell

CYP17A1:

cytochrome P450 17A1

DBD:

DNA-binding domain

DHT:

dihydrotestosterone

GR:

glucocorticoid receptor

HSPC:

hormone-sensitive prostate cancer

LBD:

ligand-binding domain

NTD:

N-terminal domain

PFS:

progression-free survival

PR:

progesterone receptor

OS:

overall survival

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    Authors and Affiliations

    1. Brady Urological Institute, Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

      John L. Silberstein & Maritza N. Taylor

    2. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA

      Emmanuel S. Antonarakis

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    Correspondence to Emmanuel S. Antonarakis.

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    John L. Silberstein and Maritza N. Taylor declare no potential conflicts of interest. Emmanuel S. Antonarakis has served as a paid consultant/advisor for Janssen, Astellas, Sanofi, Dendreon, Essa, and Medivation; he has received research funding from Janssen, Johnson & Johnson, Sanofi, Dendreon, Exelixis, Genentech, Novartis, and Tokai; he is a co-inventor of a technology that has been licensed to Tokai.

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    This article is part of the Topical Collection on Prostate Cancer

    John L. Silberstein and Maritza N. Taylor contributed equally to this work.

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    Silberstein, J.L., Taylor, M.N. & Antonarakis, E.S. Novel Insights into Molecular Indicators of Response and Resistance to Modern Androgen-Axis Therapies in Prostate Cancer. Curr Urol Rep 17, 29 (2016). https://doi.org/10.1007/s11934-016-0584-4

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