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.

Continued androgen signalling inhibition improves cabazitaxel efficacy in prostate cancer

“…Taxanes represent a vital therapeutic option for CRPC, however, treatment efficacy is limited by intrinsic and acquired resistance [5]. We showed that testosterone supplementation strongly impairs the activity of both docetaxel and cabazitaxel in vivo [6,7]. Moreover, stimulating AR signalling by testosterone was able to counteract docetaxel induced long-term tumour regression, demonstrating that AR signalling directly contributed to taxane resistance.…”

“…The current study is in compliance with the Arrive guidelines. Group size and experimental set-up were based on pilot experiments or previous studies using taxane treatment in vivo [7]. All operations (tumour inoculation, blood sampling) were conducted under adequate anaesthesia to minimize animal discomfort as described previously [6].…”

“…Once tumours surpassed 150 mm 3 , mice were stratified to receive daily enzalutamide (60 mg/kg) treatment or vehicle control, then all mice received a single intravenous administration of cabazitaxel at tumour volume 750 mm 3 at 10 mg/kg. Histology of the VCaP-Enza-B tumours and expression of the AR and cell cycle marker Ki67 were subsequently investigated by immunohistochemistry as described previously [7].…”

“…The experimental set-up was similar as described above with the following adaptations: mice were stratified to a 2:1 ratio to receive daily enzalutamide treatment or vehicle control for seven days and were subsequently sacrificed and tumour xenografts snapfrozen. Total RNA was isolated from tumour xenografts as described previously [7]. Library Prep was performed using the NEBNext Ultra Directional RNA Kit for Illumina according to the protocol "NEBNext Ultra Directional RNA Library Prep Kit for Illumina" (NEB #E7420S/L).…”

Cabazitaxel multiple rechallenges in metastatic castration‐resistant prostate cancer

“…This androgen level in microenvironment could explain docetaxel lost of activity due to difficulties for tumoral penetration. 14 Cabazitaxel shows a greater intra-tumoral penetration than docetaxel 15 and has been shown in preclinical models and prospective clinical studies to retain its activity in patients who have progressed with ARTA. 6,8 Retrospective design with a small sample of patients is the main limitation of our study.…”