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.

Androgen Receptor-Dependent and -Independent Mechanisms Involved in Prostate Cancer Therapy Resistance

“…In CRPC, AR mutations are found in 5–30% in tumors, CTCs, and ctDNA [53,55,57]. AR point mutations confer resistance to enzalutamide and abiraterone, but currently there is some ambiguity as to whether the spectrum of somatic mutations that confer drug resistance are different for abiraterone and enzalutamide.…”

Epigenetic basis of cancer health disparities: Looking beyond genetic differences

“…In a study that investigated molecular basis of racial disparities in prostate cancer, a set of six genes ( GSTP1, glutathione S-transferase pi-1; AR, androgen receptor; RARβ2; SPARC, secreted protein acidic and rich in cysteine; TIMP3, tissue inhibitor of metalloproteinase 3 and NKX2-5, NK2 homeobox-5 ) was chosen based on the reports on their hypermethylation in patient samples [76]. AR signaling, central to prostate cancer progression [77], is known to be epigenetically regulated [78]. The tumor suppressor RARβ2 , similar to its hypermethylation in breast cancer [54, 79], cervical cancer [53] and leukemia [80], is significantly more hypermethylated in prostate cancer patients, and correlates with increased tumor risk [81].…”

Crosstalk of the Androgen Receptor with Transcriptional Collaborators: Potential Therapeutic Targets for Castration-Resistant Prostate Cancer

“…In ADT, the testosterone level is too low for the AR to inhibit these genes, but is still sufficient to stimulate AR signaling in CRPC [18]. Furthermore, deregulation of the interplay of AR with AR collaborating factors commonly occurs in CRPC cells [19]. …”