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

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Androgen receptor (AR) signaling fuels prostate cancer growth and resistance to therapy.
• Docetaxel combined with androgen deprivation therapy shows promise in hormone-sensitive prostate cancer.
• The impact of testosterone and AR signaling on docetaxel efficacy in castration-resistant prostate cancer (CRPC) remains unclear.

Purpose of the Study:

• To investigate the interference of testosterone and AR signaling with docetaxel treatment in CRPC.
• To elucidate the mechanisms by which testosterone affects docetaxel accumulation and activity.

Main Methods:

• Utilized a CRPC model to assess docetaxel tumor accumulation and antitumour activity under testosterone supplementation.
• Investigated the role of the drug transporter OATP1B3 in testosterone's competition with docetaxel.
• Evaluated the impact of AR pathway activation on docetaxel efficacy and long-term tumor regression in vivo.

Main Results:

• Testosterone supplementation significantly reduced docetaxel tumor accumulation, leading to diminished tubulin stabilization and antitumour effects.
• Testosterone competed with docetaxel for uptake via the OATP1B3 transporter.
• AR signaling activation counteracted docetaxel efficacy, even independent of tubulin stabilization, and could reverse established tumor regression.

Conclusions:

• Optimizing docetaxel efficacy in CRPC requires suppression of androgen levels and AR signaling.
• Combining targeted therapeutics with docetaxel to achieve maximum AR signaling suppression is supported for CRPC treatment.