Androgen receptor signalling impairs docetaxel efficacy in castration-resistant prostate cancer
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Published:2020-09-29
Issue:12
Volume:123
Page:1715-1719
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ISSN:0007-0920
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Container-title:British Journal of Cancer
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language:en
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Short-container-title:Br J Cancer
Author:
Mout Lisanne, Moll Jan M., Chen Mingqing, de Morrée Eleonora S., de Ridder Corrina M. A., Gibson Alice, Stuurman Debra, Aghai Ashraf, Erkens-Schulze Sigrun, Mathijssen Ron H. J., Sparreboom AlexORCID, de Wit Ronald, Lolkema Martijn P.ORCID, van Weerden Wytske M.ORCID
Abstract
AbstractAndrogen 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.
Funder
Sanofi Merck Bayer Servier Janssen Pharmaceuticals
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology
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