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.

• Authors: Lisanne Mout, Jan M Moll, Mingqing Chen, Eleonora S de Morrée, Corrina M A de Ridder, Alice Gibson, Debra Stuurman, Ashraf Aghai, Sigrun Erkens-Schulze, Ron H J Mathijssen, Alex Sparreboom, Ronald de Wit, Martijn P Lolkema, Wytske M van Weerden
• Journal: British journal of cancer (Br J Cancer) Vol. 123 Issue 12 Pg. 1715-1719 (12 2020) ISSN: 1532-1827 [Electronic] England
• PMID: 32989230 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Androgen Antagonists
• Androgen Receptor Antagonists
• Antineoplastic Agents
• Neoplasm Proteins
• Receptors, Androgen
• SLCO1B3 protein, human
• Solute Carrier Organic Anion Transporter Family Member 1B3
• Tubulin
• Docetaxel
• Testosterone
• Prostate-Specific Antigen

Topics

• Acetylation
• Androgen Antagonists (pharmacokinetics, therapeutic use)
• Androgen Receptor Antagonists (therapeutic use)
• Animals
• Antineoplastic Agents (pharmacokinetics, therapeutic use)
• Cell Death
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Cell Survival
• Disease Progression
• Docetaxel (pharmacokinetics, therapeutic use)
• Drug Interactions
• Drug Resistance, Neoplasm (physiology)
• Humans
• In Situ Nick-End Labeling
• Male
• Mice
• Mice, Nude
• Neoplasm Proteins (metabolism)
• Neoplasm Transplantation
• Prostate-Specific Antigen (biosynthesis)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, metabolism, pathology)
• Receptors, Androgen (drug effects, metabolism)
• Signal Transduction (drug effects)
• Solute Carrier Organic Anion Transporter Family Member 1B3 (metabolism)
• Testosterone (administration & dosage, antagonists & inhibitors, metabolism, pharmacology)
• Tubulin (drug effects, metabolism)