Intracrine androgen biosynthesis and drug resistance

Abstract

Castration-resistant prostate cancer is the lethal form of prostate cancer and most commonly remains dependent on androgen receptor (AR) signaling. Current therapies use AR signaling inhibitors (ARSI) exemplified by abiraterone acetate, a P450c17 inhibitor, and enzalutamide, a potent AR antagonist. However, drug resistance to these agents occurs within 12-18 months and they only prolong overall survival by 3-4 months. Multiple mechanisms can contribute to ARSI drug resistance. These mechanisms can include but are not limited to germline mutations in the AR, post-transcriptional alterations in AR structure, and adaptive expression of genes involved in the intracrine biosynthesis and metabolism of androgens within the tumor. This review focuses on intracrine androgen biosynthesis, how this can contribute to ARSI drug resistance, and therapeutic strategies that can be used to surmount these resistance mechanisms.

Keywords: Prostate cancer; abiraterone acetate; aldo-keto reductase 1C3; androgen biosynthesis; enzalutamide.

Figure 1

Intracrine androgen biosynthesis. Top panel shows reactions that occur in the adrenal reticularis. Bottom panel shows the conversion of adrenal steroids into the potent androgens testosterone and 5α-DHT in human prostate. The classical or canonical pathway is shown in red; the 5α-adione pathway is shown in blue; the backdoor pathway from allopregnanlone is shown in purple; the alternative pathway from 5-androstenediol is also shown. All enzymes are listed in italics by their gene names as follows: AKR1C1, 3α(20α)-hydroxysteroid dehydrogenase; AKR1C2, type 3 3α-hydroysteroid dehydrogenase; AKR1C3, type 5 17β-hydroxysteroid dehydrogenase; CYP17A1, 17α-hydroxylase17/20 lyase; HSD3B1, type 1 3β-hydroxysteroid dehydrogenase; HSD17B2 and 17HSD17B4, type 2 and type 4 17β-hydroxysteroid dehydrogenase; HSD17B6, type 6 17β-hydroxysteroid dehydrogenase and retinol dehydrogenase; and SRD5A1/2, type 1 and type 2 steroid 5α-reductase

Figure 2

Conversion of 11-oxygenated androgens to 11-keto-Testosterone and 11-keto-DHT. The pathway from adrenal 11β-hydroxy-⁴AD and 11-keto-⁴AD to 11-keto-testosterone and 11-Keto-DHT, respectively is shown. The enzymes implicated in this conversion in the prostate are shown. All enzymes are listed in italics by their gene names. AKR1C3, type 5 17β-hydroxysteroid dehydrogenase; HSD11B2, type 2 11β-hydroxysteroid dehydrogenase; and SRD5A1/2, type 1 and type 2 steroid 5α-reductase

Figure 3

Mechanisms of drug resistance to androgen receptor signaling inhibitors (ARSI). Following uptake of DHEA-SO₄ into the prostate by SLCO transporters a number of enzymes with either increased expression or germline mutations that result in increased activity/stability may contribute to ARSI drug therapy resistance (shown in green); similarly, a number of enzymes with either decreased activity or germline mutations that decrease activity/stability may contribute to drug resistance (shown in red). AKR1C3 may be an exception in that it is highly upregulated by androgen deprivation, and nsSNPs in conserved positions may reduce its activity. All enzymes are listed in italics by their gene names as described in the legends to Figures 1 and 2

Figure 4

Putative Coactivator Domain of AKR1C3. Ribbon diagram of the AKR1C3•NADP⁺•Indomethacin complex (taken from PDB ID: 3UGB) showing the putative coactivator domain in the enzyme. Protein fold (green); NADP+ stick representation (red); indomethacin stick representation (orange); blue corresponds to amino acids 171-237; the disordered loop that may bind to the N-terminus of the AR (magneta). Cartoon prepared in PyMol