Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects

Abstract

Androgen receptor (AR) signaling is a critical pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. However, over time, most tumors become resistant to ADT. The view of castration-resistant prostate cancer (CRPC) has changed dramatically in the last several years. Progress in understanding the disease biology and mechanisms of castration resistance led to significant advancements and to paradigm shift in the treatment. Accumulating evidence showed that prostate cancers develop adaptive mechanisms for maintaining AR signaling to allow for survival and further evolution. The aim of this review is to summarize molecular mechanisms of castration resistance and provide an update in the development of novel agents and strategies to more effectively target the AR signaling pathway.

Figure 1

Schematic structure of human AR and AR splice variant 7 (AR-V7) and 567(AR567es). (a) The human AR gene consists of eight exons with exon 1 encoding the N-terminal domain (NTD) and the entire 5′ untranslated region; exons 2 and 3 encoding the DNA-binding domain (DBD); and exons 4–8 encoding the ‘hinge’ region (HR) and ligand binding domain (LBD). The NTD contains the activation function 1 (AF-1) that includes two overlapping transcription activation units (TAU): TAU-1 (amino acids 1–370), which supports AR transcriptional activity upon stimulation by full agonist, and TAU-5 (amino acids 360–528), which confers constitutive activity to the AR in the absence of the LBD. The central region of the receptor contains the DBD and the HR and harbors the nuclear localization signal (NLS). The DBD is comprised of two cysteine-rich zinc finger motifs consisting of three alpha-helixes and a carboxy terminal extension (CTE) extending into the flexible hinge region. The first zinc finger defines DNA binding specificity, whereas the second zinc finger facilitates receptor dimerization and stabilization of the DNA-receptor complex. The carboxy-terminal end contains the LBD and the AF-2 function; (b) AR-V7 (also named AR3) encodes a protein with exons 1–3 and a terminal cryptic exon (CE3); (c) AR567es encodes a protein comprised of exons 1–4, and because of a frame-shift due to loss of exons 5–7, exon 8 has a stop codon generated after the first 10 amino acids resulting in a shortened exon 8.

Figure 2

Canonical and alternative androgen biosynthesis pathways. Androgens are synthesized from cholesterol via multiple enzymatic steps, most of which are catalyzed by members of the cytochrome P450 (CYP) family. CYP11A1 is responsible for side chain cleavage of cholesterol, converting cholesterol to pregnenolone. Pregnenolone is then metabolized to dehydro-epiandrosterone (DHEA) and androstenedione (AD) via CYP17A1, which catalyzes both the 17 α-hydroxylation and the subsequent 17,20-lyase cleavage. The ‘canonical pathway’ for testosterone synthesis involves conversion of the major adrenal androgen DHEA and AD to testosterone in the testis, followed by irreversible 5α-reduction of testosterone to the higher affinity ligand DHT by 5α-reductases (SRD5A). 5α-reduction of upstream steroids, as opposed to 5α-reduction of testosterone, leads to DHT synthesis that bypasses testosterone through at least two pathways. In the ‘androstanedione pathway’, AD may be converted to 5-androstanedione by SRD5A that can then be converted into DHT by 17βHSD(s). Another alternative pathway to DHT occurs when 17-hydroxyprogesterone accumulates and SRD5A enzymes are present. In this alternative or ‘backdoor’ pathway, 17-hydroxyprogesterone is 5α- and 3α- reduced before the 17,20-lyase reaction of CYP17A1, yielding the 5α-reduced androgen androsterone. This pathway yields DHT without using DHEA, AD and testosterone as intermediates.