Biologic and clinical significance of androgen receptor variants in castration resistant prostate cancer

Abstract

As prostate cancer progresses to the lethal castration resistant and metastatic form, genetic and epigenetic adaptation, clonal selection, and evolution of the tumor microenvironment contribute to the emergence of unique biologic characteristics under the selective pressure of external stresses. These stresses include the therapies applied in the clinic or laboratory and the exposures of cancers to hormonal, paracrine, or autocrine stimuli in the context of the tumor micro- and macro-environment. The androgen receptor (AR) is a key gene involved in prostate cancer etiology and oncogenesis, including disease development, progression, response to initial hormonal therapies, and subsequent resistance to hormonal therapies. Alterations in the AR signaling pathway have been observed in certain selection contexts and contribute to the resistance to agents that target hormonal regulation of the AR, including standard androgen deprivation therapy (ADT), anti-androgens such as enzalutamide, and androgen synthesis inhibition with abiraterone acetate. One such resistance mechanism is the synthesis of constitutively active AR variants lacking the canonical ligand binding domain. This review focuses on the etiology, characterization, biologic properties, and emerging data contributing to the clinical characteristics of AR variants, and suggests approaches to full-length AR and AR variant biomarker validation, assessment, and systemic targeting in the clinic.

Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)

“…AR-V7 is transcribed from alternatively spliced transcripts of AR mRNA (48). Although not fully understood, BETi have been shown to regulate expression of splicing factors possibly key to AR-V7 generation (30,49).…”

Androgen Signaling in Prostate Cancer

“…It is thought that AR-Vs may emerge through aberrant alternative splicing (Liu et al 2014) or AR gene rearrangements (Li et al , 2012 to escape antiandrogen therapies that target the LBD. Although more than 20 AR-Vs have now been confirmed in prostate cancer specimens (Robinson et al 2015), which show different levels of transcriptional activity and expression (Ware et al 2014;Lu et al 2015), AR-V7 is the most commonly detected variant in CRPC (Ware et al 2014). Truncation of AR-V7 occurs after exon 3 and includes a cryptic exon 3b from an intron into the expressed protein (Fig.…”

Exploring the Clinical Benefit of Docetaxel or Enzalutamide After Disease Progression During Abiraterone Acetate and Prednisone Treatment in Men With Metastatic Castration-Resistant Prostate Cancer

“…Indeed, AR-V7 may promote docetaxel resistance, since it does not depend on microtubular transport to enter the nucleus 16 . Other AR-M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 5 variants, such as AR-v567, may also be clinically relevant for AA-enzalutamide cross resistance, but appear to be associated with taxane sensitivity 16,17 . Additional mechanisms that may promote AA-enzalutamide cross resistance include glucocorticoid receptor activation of the AR transcriptome 18 , AR mutations that promote enzalutamide agonism 19,20 , neuroendocrine transformation 21,22 , or activation of other oncogenic pathways 23 .…”