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Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy



Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis1,2. Abiraterone is metabolized in patients to Δ4-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5α-reductase substrates, such as testosterone3. Here, we show that D4A is converted to at least three 5α-reduced and three 5β-reduced metabolites in human serum. The initial 5α-reduced metabolite, 3-keto-5α-abiraterone, is present at higher concentrations than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while D4A concentrations rose, showing that dutasteride effectively blocks production of a tumour-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy.

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Figure 1: Genesis of 5α- and 5β-reduced Abi metabolites in patients treated with Abi acetate.
Figure 2: Effects of 5α-reduced Abi metabolites on the androgen pathway and tumour progression.
Figure 3: Long-term exposure to Abi and D4A leads to an increase in SRD5A expression and enzymatic activity and an increase in conversion from D4A to 5α-reduced Abi metabolites.
Figure 4: In patients treated with Abi acetate, SRD5A inhibition significantly increases serum D4A and specifically and significantly depletes all three 5α-Abi metabolites in serum.

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Gene Expression Omnibus

Data deposits

Microarray results have been deposited in the NCBI Gene Expression Omnibus database under accession number GSE75387.


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We thank T. Penning for use of the AKR1C2 construct and D. Russell for LY191704. This work was supported in part by funding from a Howard Hughes Medical Institute Physician-Scientist Early Career Award (to N.S.), a Prostate Cancer Foundation Challenge Award (to N.S.), an American Cancer Society Research Scholar Award (12-038-01-CCE; to N.S.), grants from the National Cancer Institute (R01CA168899, R01CA172382, and R01CA190289; to N.S.), a grant from the US Army Medical Research and Materiel Command (PC121382 to Z.L.), a Prostate Cancer Foundation Young Investigator Award (to Z.L.), grants from the National Cancer Institute (P01 CA163227 and P50 CA090381), and a Prostate Cancer Foundation Challenge Award (to S.P.B.). Janssen provided clinical trial support (to M.-E.T.).

Author information

Authors and Affiliations



Z.L. performed gene expression, metabolism and mouse work. M. Alyamani performed mass spectrometry metabolism work. J.L. performed immunoblots. S.K.U. performed chemical syntheses. K.R. and M. Abazeed performed the microarray GSEA analysis. M.-E.T. and S.P.B. designed and performed the clinical trial. Z.L., M. Alaymani, R.J.A. and N.S. designed the studies and wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Nima Sharifi.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Synthesis of abiraterone metabolites.

a, Synthesis of 5α-Abi, 3α-hydroxy-5α-Abi and 3β-hydroxy-5α-Abi. b, Synthesis of 5β-Abi, 3α-hydroxy-5β-Abi and 3β-hydroxy-5β-Abi. c, Synthesis of D4A.

Extended Data Figure 2 Genesis and interconversion of Abi metabolites.

a, C4-2 cells. b, VCaP cells. Cells were treated with abiraterone or the indicated metabolite (0.1 μM) for 24 or 48 h and each of the indicated metabolites was detected by LC–MS/MS in triplicate. Error bars represent s.d.

Extended Data Figure 3 In vitro time course formation of 5α-reduced Abi metabolites.

ac, Conversion from D4A to 5α-reduced abiraterone metabolites (a), 3-keto reduction of 5α-Abi to 3α-OH-5α-Abi (b), and 3α-OH-oxidation of 3α-OH-5α-Abi to 5α-Abi (c) is detectable in LNCaP and LAPC4 prostate cancer cell lines. Cells were treated with 10 μM of the indicated compounds, metabolites were separated by HPLC and quantified by UV spectroscopy. Experiments were performed in triplicate at least three times and error bars represent s.d. d, Examples of HPLC and UV absorption tracings for incubations of prostate cancer cell lines with D4A, 5α-Abi and 3α-OH-5α-Abi.

Extended Data Figure 4 Clinical presence of 5α-reduced and 5β-reduced Abi metabolites in patients treated with Abi acetate.

a, Dot plot of Abi and its metabolites expressed as the percentage of the total of Abi and its metabolites. b, LC–MS/MS separation of Abi metabolite standards and an example from serum obtained from a patient being treated with Abi.

Extended Data Figure 5 Enzymes involved in the formation of 5α-reduced Abi metabolites.

a, 3βHSD1 catalyses the conversion of Abi to D4A and downstream accumulation of 5α-Abi and 3α-OH-5α-Abi. LAPC4 cells were transiently transfected with the indicated amount of an expression construct encoding 3βHSD1 or vector control before treatment with Abi. b, Conversion of D4A to 5α-Abi is catalysed by SRD5A1 or SRD5A2. The indicated amounts of SRD5A1, SRD5A2, or empty vector plasmids were transfected into 293T cells, and cells were incubated with D4A for the designated incubation times. c, SRD5A1 silencing blocks 5α-reduction of D4A. LAPC4 cells stably expressing short hairpin (sh)RNAs targeting SRD5A1 or nonsilencing control were treated with D4A and metabolites for the indicated times. d, Pharmacological SRD5A inhibition blocks 5α-reduction of D4A. LAPC4 cells were treated with D4A and the SRD5A inhibitors dutasteride or LY191704. A parallel control experiment is shown with inhibition of 5α-reduction of [3H]androstenedione (AD). e, Conversion of 5α-Abi to 3α-OH-5α-Abi is catalysed by AKR1C2. 293T cells were transfected with AKR1C2 or empty vector and treated with 5α-Abi for the indicated times. For all experiments, metabolites were separated by HPLC and quantified by UV spectroscopy (Abi metabolites) or with a beta-RAM ([3H]androgens). Error bars represent s.d. All experiments were performed at least three times.

Extended Data Figure 6 Gene expression profile of stimulation by 5α-Abi and DHT.

a, Unbiased pathway analysis of 5α-abi-regulated genes. b, Gene Set Enrichment Analysis of 5α-abi-regulated genes with the androgen receptor signature gene set. c, Gene expression in LAPC4 cells stimulated by 1 μM 5α-Abi or 0.1 nM DHT for 48 h. Regulated genes were determined by detection P < 0.01, upregulation > 1.55 or downregulation < 0.5 compared with vehicle control group. d, Venn diagram of 5α-abi and DHT-regulated genes.

Extended Data Figure 7 Transcript expression regulation in the presence of Abi, D4A or enzalutamide.

a, SRD5A1 and SRD5A2 expression in VCaP cells treated with Abi or D4A as indicated in Fig. 3. b, SRD5A1 and SRD5A2 expression does not change with enzalutamide (Enz) treatment. c, SRD5A1 protein abundance does not change with enzalutamide treatment in LAPC4 or VCaP cells. d, AR-V7 expression is unchanged in LNCaP cells treated with Abi or D4A as indicated in Fig. 3. Expression was normalized to RPLPO and vehicle-treated cells for all comparisons. Error bars represent s.d.

Extended Data Table 1 Data for each of the 12 patients treated with Abi acetate
Extended Data Table 2 Genes regulated by 5α-abi
Extended Data Table 3 Concentrations of Abi and its metabolites in a phase II clinical trial (NCT01393730)

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Li, Z., Alyamani, M., Li, J. et al. Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy. Nature 533, 547–551 (2016).

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