Androgen receptor signalling impairs docetaxel efficacy in castration-resistant prostate cancer

Lisanne Mout; Matthijs Moll; M Chen; Ellen Morrée; Corrina de Ridder; A Gibson; Debra Stuurman; Ashraf Jozefzoon - Aghai; Sigrun Erkens - Schulze; Ron Mathijssen; A Sparreboom; Ronald de Wit; Martijn Lolkema; Wytske van Weerden

doi:10.1038/s41416-020-01105-y

Androgen receptor signalling impairs docetaxel efficacy in castration-resistant prostate cancer

Lisanne Mout, Matthijs Moll, M Chen, Ellen Morrée, Corrina de Ridder, A Gibson, Debra Stuurman, Ashraf Jozefzoon - Aghai, Sigrun Erkens - Schulze, Ron Mathijssen, A Sparreboom, Ronald de Wit, Martijn Lolkema, Wytske van Weerden^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Androgen receptor (AR) signalling drives neoplastic growth and therapy resistance in prostate cancer. Recent clinical data show that docetaxel combined with androgen deprivation therapy improves outcome in hormone-sensitive disease. We studied whether testosterone and AR signalling interferes with docetaxel treatment efficacy in castration-resistant prostate cancer (CRPC). We found that testosterone supplementation significantly impaired docetaxel tumour accumulation in a CRPC model, resulting in decreased tubulin stabilisation and antitumour activity. Furthermore, testosterone competed with docetaxel for uptake by the drug transporter OATP1B3. Irrespective of docetaxel-induced tubulin stabilisation, AR signalling by testosterone counteracted docetaxel efficacy. AR-pathway activation could also reverse long-term tumour regression by docetaxel treatment in vivo. These results indicate that to optimise docetaxel efficacy, androgen levels and AR signalling need to be suppressed. This study lends evidence for continued maximum suppression of AR signalling by combining targeted therapeutics with docetaxel in CRPC.

Original language	English
Pages (from-to)	1715-1719
Number of pages	5
Journal	British Journal of Cancer
Volume	123
Issue number	12
DOIs	https://doi.org/10.1038/s41416-020-01105-y
Publication status	Published - 8 Dec 2020

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Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Cancer Research UK.

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Mout, L., Moll, M., Chen, M., Morrée, E., de Ridder, C., Gibson, A., Stuurman, D., Jozefzoon - Aghai, A., Erkens - Schulze, S., Mathijssen, R., Sparreboom, A., de Wit, R., Lolkema, M., & van Weerden, W. (2020). Androgen receptor signalling impairs docetaxel efficacy in castration-resistant prostate cancer. British Journal of Cancer, 123(12), 1715-1719. https://doi.org/10.1038/s41416-020-01105-y

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title = "Androgen receptor signalling impairs docetaxel efficacy in castration-resistant prostate cancer",

abstract = "Androgen receptor (AR) signalling drives neoplastic growth and therapy resistance in prostate cancer. Recent clinical data show that docetaxel combined with androgen deprivation therapy improves outcome in hormone-sensitive disease. We studied whether testosterone and AR signalling interferes with docetaxel treatment efficacy in castration-resistant prostate cancer (CRPC). We found that testosterone supplementation significantly impaired docetaxel tumour accumulation in a CRPC model, resulting in decreased tubulin stabilisation and antitumour activity. Furthermore, testosterone competed with docetaxel for uptake by the drug transporter OATP1B3. Irrespective of docetaxel-induced tubulin stabilisation, AR signalling by testosterone counteracted docetaxel efficacy. AR-pathway activation could also reverse long-term tumour regression by docetaxel treatment in vivo. These results indicate that to optimise docetaxel efficacy, androgen levels and AR signalling need to be suppressed. This study lends evidence for continued maximum suppression of AR signalling by combining targeted therapeutics with docetaxel in CRPC.",

author = "Lisanne Mout and Matthijs Moll and M Chen and Ellen Morr{\'e}e and {de Ridder}, Corrina and A Gibson and Debra Stuurman and {Jozefzoon - Aghai}, Ashraf and {Erkens - Schulze}, Sigrun and Ron Mathijssen and A Sparreboom and {de Wit}, Ronald and Martijn Lolkema and {van Weerden}, Wytske",

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Mout, L, Moll, M, Chen, M, Morrée, E, de Ridder, C, Gibson, A, Stuurman, D, Jozefzoon - Aghai, A, Erkens - Schulze, S , Mathijssen, R, Sparreboom, A, de Wit, R , Lolkema, M & van Weerden, W 2020, 'Androgen receptor signalling impairs docetaxel efficacy in castration-resistant prostate cancer', British Journal of Cancer, vol. 123, no. 12, pp. 1715-1719. https://doi.org/10.1038/s41416-020-01105-y

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T1 - Androgen receptor signalling impairs docetaxel efficacy in castration-resistant prostate cancer

AU - Mout, Lisanne

AU - Moll, Matthijs

AU - Chen, M

AU - Morrée, Ellen

AU - de Ridder, Corrina

AU - Gibson, A

AU - Stuurman, Debra

AU - Jozefzoon - Aghai, Ashraf

AU - Erkens - Schulze, Sigrun

AU - Mathijssen, Ron

AU - Sparreboom, A

AU - de Wit, Ronald

AU - Lolkema, Martijn

AU - van Weerden, Wytske

PY - 2020/12/8

Y1 - 2020/12/8

N2 - Androgen receptor (AR) signalling drives neoplastic growth and therapy resistance in prostate cancer. Recent clinical data show that docetaxel combined with androgen deprivation therapy improves outcome in hormone-sensitive disease. We studied whether testosterone and AR signalling interferes with docetaxel treatment efficacy in castration-resistant prostate cancer (CRPC). We found that testosterone supplementation significantly impaired docetaxel tumour accumulation in a CRPC model, resulting in decreased tubulin stabilisation and antitumour activity. Furthermore, testosterone competed with docetaxel for uptake by the drug transporter OATP1B3. Irrespective of docetaxel-induced tubulin stabilisation, AR signalling by testosterone counteracted docetaxel efficacy. AR-pathway activation could also reverse long-term tumour regression by docetaxel treatment in vivo. These results indicate that to optimise docetaxel efficacy, androgen levels and AR signalling need to be suppressed. This study lends evidence for continued maximum suppression of AR signalling by combining targeted therapeutics with docetaxel in CRPC.

AB - Androgen receptor (AR) signalling drives neoplastic growth and therapy resistance in prostate cancer. Recent clinical data show that docetaxel combined with androgen deprivation therapy improves outcome in hormone-sensitive disease. We studied whether testosterone and AR signalling interferes with docetaxel treatment efficacy in castration-resistant prostate cancer (CRPC). We found that testosterone supplementation significantly impaired docetaxel tumour accumulation in a CRPC model, resulting in decreased tubulin stabilisation and antitumour activity. Furthermore, testosterone competed with docetaxel for uptake by the drug transporter OATP1B3. Irrespective of docetaxel-induced tubulin stabilisation, AR signalling by testosterone counteracted docetaxel efficacy. AR-pathway activation could also reverse long-term tumour regression by docetaxel treatment in vivo. These results indicate that to optimise docetaxel efficacy, androgen levels and AR signalling need to be suppressed. This study lends evidence for continued maximum suppression of AR signalling by combining targeted therapeutics with docetaxel in CRPC.

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JO - British Journal of Cancer

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ER -

Androgen receptor signalling impairs docetaxel efficacy in castration-resistant prostate cancer

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