Current strategies for targeting the activity of androgen receptor variants

Abstract

Current therapies for advanced prostate cancer, such as enzalutamide and abiraterone, focus on inhibiting androgen receptor (AR) activity and reducing downstream signaling pathways to inhibit tumor growth. Unfortunately, cancer cells are very adaptable and, over time, these cells develop mechanisms by which they can circumvent therapeutics. One of the many mechanisms that have been discovered is the generation of AR variants. These variants are generated through alternative splicing of the full length AR and often lack the ligand binding domain. This leads to forms of the AR that are constitutively active that continue to promote prostate cancer cell growth even in the absence of ligand. The high prevalence of AR variants and their role in disease progression have prompted a number of studies investigating ways to inhibited AR variant expression and activity. Among these are the anti-helminthic drug, niclosamide, which selectively promotes degradation of AR variants over full length AR and re-sensitizes anti-androgen resistant prostate cancer cells to treatment with enzalutamide and abiraterone. Other AR variant targeting mechanisms include interfering with AR variant co-activators and the development of drugs that bind to the DNA or N-terminal AR domains, which are retained in most AR variants. The clinical efficacy of treating prostate cancer by targeting AR variants is under investigation in several clinical trials. In this review, we provide an overview of the most relevant AR variants and discuss current AR variant targeting strategies.

Nerve Growth Factor Induces Proliferation and Aggressiveness in Prostate Cancer Cells

“…Nevertheless, CRPC cell lines often harbor AR variants that lack the C-terminal ligand-binding domain. As such, these variants are frequently constitutively active, since they do not require the presence of androgens to initiate downstream AR signaling and their expression has been correlated with androgen deprivation therapy (ADT) resistance [71,72]. Thus, it cannot be excluded that the CRPC cell lines here employed express AR variants that might differentially control the NGF signaling.…”

Therapies Targeted to Androgen Receptor Signaling Axis in Prostate Cancer: Progress, Challenges, and Hope

“…The most frequent variant is AR-V7, which is resistant to abiraterone and enzalutamide [66]. Interaction of an AR coactivator Vav3 with AR-V7 is suggested to be a mechanism for CRPC where it promotes the ligand-independent transcriptional activity of AR-V7 [179,180]. Accordingly, disruption of this interaction is shown to suppress the proliferation and aggressive phenotype of CRPC cells [181].…”

Bruceantin targets HSP90 to overcome resistance to hormone therapy in castration-resistant prostate cancer

“…Targeting of full-length AR (AR-FL) and androgen synthesis is a mainstay of therapy for PCa patients. Although PCa initially responds to hormone therapies such as androgen biosynthesis inhibitors ( e.g., abiraterone [ABI]) and anti-androgens ( e.g., enzalutamide [ENZ] and bicalutamide [BIC]), PCa eventually progresses to advanced metastatic CRPC, which is resistant to conventional androgen deprivation and anti-androgen therapies 1 - 5 . Accumulating evidence indicates that alternatively spliced AR variants (AR-Vs) play critical roles in promoting resistance to ABI and ENZ therapies and in driving metastatic CRPC progression 1 - 3 , 5 .…”