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

Abstract

As prostate cancer (PCa) 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 biological 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 PCa 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, antiandrogens 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, biological 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.

Keywords: AR variants; androgen receptor; castration resistant prostate cancer; epithelial to mesenchymal transition; metastasis; splice variants.

Figure 1

AR gene rearrangements and AR variants identified in prostate cancer. A. Schematic of AR gene mutations and genomic alterations with cryptic exons indicated in red. B. Schematic of AR and variant mRNA. Functional domains represented as NH2-terminal domain (NTD) in blue, DNA binding domain (DBD) in green, hinge region in purple and ligand binding domain (LBD) in orange. Cryptic exons are colored red. Solid regions represent the open reading frame. Star indicates calpain recognition site for proteolytic cleavage. Distinct AR variants AR-V8, AR-V10 and AR-V11 are represented by one schematic.

Figure 2

A–D. Clinical associations of AR variant expression. A. Zhang et al. (Zhang et al. 2011) probed for AR protein levels using two AR-specific antibodies directed against the N- and C-termini. This allowed for the inference of AR splice variant expression in in these tissues, indicating that metastatic CRPC tissue contains a higher prevalence of N+C- or N+C-reduced expression patterns as compared to localized disease (Zhang et al. 2011). B. Using these same antibodies, Zhang et al. (Zhang et al. 2011) showed that PSA production by tumor cells appears to be reduced in some N+C-reduced tumors. C. Hornberg et al. (Hornberg et al. 2011) demonstrated by Kaplan-Meier analysis that high expression of AR -V7 in bone metastatic CRPC at surgery is associated with death from prostate cancer. D. Guo et al. (Guo et al. 2009) demonstrated that survival free of PSA recurrence was associated with expression of AR-V7 (AR3) in localized prostate cancer. Reprinted by permission from the American Association for Cancer Research: Guo Z et al., A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Research, March 15, 2009, 69(6), 2305–2313, doi:10.1158/0008-5472.