Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer

Zhenfei Li, Andrew C. Bishop, Mohammad Alyamani, Jorge A. Garcia, Robert Dreicer, Dustin Bunch, Jiayan Liu, Sunil K. Upadhyay, Richard J. Auchus, Nima Sharifi

Research output: Contribution to journalArticle

142 Citations (Scopus)

Abstract

Prostate cancer resistance to castration occurs because tumours acquire the metabolic capability of converting precursor steroids to 5α-dihydrotestosterone (DHT), promoting signalling by the androgen receptor and the development of castration-resistant prostate cancer. Essential for resistance, DHT synthesis from adrenal precursor steroids or possibly from de novo synthesis from cholesterol commonly requires enzymatic reactions by 3β-hydroxysteroid dehydrogenase (3βHSD), steroid-5α-reductase (SRD5A) and 17β-hydroxysteroid dehydrogenase (17βHSD) isoenzymes. Abiraterone, a steroidal 17α-hydroxylase/17,20-lyase (CYP17A1) inhibitor, blocks this synthetic process and prolongs survival. We hypothesized that abiraterone is converted by an enzyme to the more active Δ<sup>4</sup> -abiraterone (D4A), which blocks multiple steroidogenic enzymes and antagonizes the androgen receptor, providing an additional explanation for abiraterone's clinical activity. Here we show that abiraterone is converted to D4A in mice and patients with prostate cancer. D4A inhibits CYP17A1, 3βHSD and SRD5A, which are required for DHT synthesis. Furthermore, competitive androgen receptor antagonism by D4A is comparable to the potent antagonist enzalutamide. D4A also has more potent anti-tumour activity against xenograft tumours than abiraterone. Our findings suggest an additional explanation - conversion to a more active agent - for abiraterone's survival extension. We propose that direct treatment with D4A would be more clinically effective than abiraterone treatment.

Original languageEnglish (US)
Pages (from-to)347-351
Number of pages5
JournalNature
Volume523
Issue number7560
DOIs
StatePublished - Jul 16 2015

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Prostatic Neoplasms
Dihydrotestosterone
Neoplasms
Androgen Receptors
3-Hydroxysteroid Dehydrogenases
Steroids
Castration
Oxidoreductases
Steroid 17-alpha-Hydroxylase
Survival
abiraterone
Enzymes
Mixed Function Oxygenases
Heterografts
Isoenzymes
Cholesterol
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Li, Z., Bishop, A. C., Alyamani, M., Garcia, J. A., Dreicer, R., Bunch, D., ... Sharifi, N. (2015). Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. Nature, 523(7560), 347-351. https://doi.org/10.1038/nature14406

Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. / Li, Zhenfei; Bishop, Andrew C.; Alyamani, Mohammad; Garcia, Jorge A.; Dreicer, Robert; Bunch, Dustin; Liu, Jiayan; Upadhyay, Sunil K.; Auchus, Richard J.; Sharifi, Nima.

In: Nature, Vol. 523, No. 7560, 16.07.2015, p. 347-351.

Research output: Contribution to journalArticle

Li, Z, Bishop, AC, Alyamani, M, Garcia, JA, Dreicer, R, Bunch, D, Liu, J, Upadhyay, SK, Auchus, RJ & Sharifi, N 2015, 'Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer', Nature, vol. 523, no. 7560, pp. 347-351. https://doi.org/10.1038/nature14406
Li Z, Bishop AC, Alyamani M, Garcia JA, Dreicer R, Bunch D et al. Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. Nature. 2015 Jul 16;523(7560):347-351. https://doi.org/10.1038/nature14406
Li, Zhenfei ; Bishop, Andrew C. ; Alyamani, Mohammad ; Garcia, Jorge A. ; Dreicer, Robert ; Bunch, Dustin ; Liu, Jiayan ; Upadhyay, Sunil K. ; Auchus, Richard J. ; Sharifi, Nima. / Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. In: Nature. 2015 ; Vol. 523, No. 7560. pp. 347-351.
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