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Review
. 2015 Sep:153:105-13.
doi: 10.1016/j.jsbmb.2015.05.010. Epub 2015 May 29.

Mechanisms of drug resistance that target the androgen axis in castration resistant prostate cancer (CRPC)

Trevor M Penning  1
Affiliations
Review

Mechanisms of drug resistance that target the androgen axis in castration resistant prostate cancer (CRPC)

Trevor M Penning. J Steroid Biochem Mol Biol. 2015 Sep.

Abstract

Castrate resistant prostate cancer (CRPC) is the fatal-form of prostate cancer and remains androgen dependent. The reactivation of the androgen axis occurs due to adaptive intratumoral androgen biosynthesis which can be driven by adrenal androgens and/or by changes in the androgen receptor (AR) including AR gene amplification. These mechanisms are targeted with P450c17 inhibitors e.g., abiraterone acetate and AR super-antagonists e.g., enzalutamide, respectively. Clinical experience indicates that with either agent an initial response is followed by drug resistance and the patient clinically progresses on these agents. This article reviews the mechanisms of intrinsic and acquired drug resistance that target the androgen axis and how this might be surmounted.

Keywords: Androgen receptor; Prostate cancer; Steroidogenesis; Therapeutics.

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Figures

Figure 1
Figure 1
Composite Mechanisms of Drug Resistance in Castration Resistant Prostate Cancer. Mechanisms indicated in red boxes; arrow between AR-FL and AR-SV and AR-SM indicates selection pressure to produce new AR subtypes; where AR-FL, androgen receptor full length; AR-SV, androgen receptor splice variant; AR-M, mutated androgen receptor. italics = gene names; AKR1C3, aldo-keto reductase 1C3; AR-SV, = androgen receptor splice variant; AR-M, = mutated androgen receptor; CYP17A1, DHEA = dehydroepiandrosterone; Δ4-AD, 4-androstene-3,17-dione; Adione, = 5α-androstane-3,17-dione; Δ5-Adiol, 5-androstene-3β,17β-diol; DHT, 5α-dihydrotestosterone; 3α-Adiol, 5α-androstane-3α,17β-diol; HSD3B1; 3β-hydroxysteroid dehydrogenase type 1; P450c17 (17α-hydroxylase,17/20-lyase); T =testosterone; SLCO; = solute carrier organic anion transporter;
Figure 2
Figure 2
Domains of AR-SVs. Numbers refer to AR gene exons.
See this image and copyright information in PMC

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