title: Cross-resistance between taxanes and new hormonal agents abiraterone and enzalutamide may affect drug sequence choices in metastatic castration-resistant prostate cancer.
abstract: BACKGROUND
  Treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) have expanded in recent years with the introduction of cabazitaxel, abiraterone and enzalutamide. With new systemic therapies available, the optimal treatment sequence of these drugs in mCRPC becomes increasingly important. As shown recently, patients who had previously been treated with abiraterone showed impaired responses to docetaxel, suggesting clinical cross-resistance [1]. In the present study, we aimed to identify cross-resistance between taxanes (docetaxel and cabazitaxel) and the new hormonal agents abiraterone and enzalutamide. As a potential mechanism for cross-resistance, we investigated the effects on androgen receptor (AR) nuclear translocation of these compounds.
  
  
  METHODS
  To identify cross-resistance, we determined the effects of docetaxel, cabazitaxel, abiraterone and enzalutamide on cell viability in prostate cancer cell lines with acquired resistance to abiraterone and enzalutamide. Time-lapse confocal microscopy was used to study the dynamics of AR nuclear translocation.
  
  
  RESULTS
  We observed impaired efficacy of docetaxel, cabazitaxel and enzalutamide in the abiraterone-resistant cell line, compared to the non-resistant cell line, providing evidence for in vitro cross-resistance. Impaired efficacy of docetaxel, cabazitaxel and abiraterone was observed in the enzalutamide-resistant cell line. Furthermore, docetaxel and cabazitaxel inhibited AR nuclear translocation, which was also observed for abiraterone and enzalutamide.
  
  
  CONCLUSIONS
  In conclusion we found substantial preclinical evidence for cross-resistance between the taxanes docetaxel and cabazitaxel, and AR targeting agents abiraterone and enzalutamide. Since these compounds all interfere with AR-signalling, this strongly suggests a common mechanism of action, and thus a potential mechanism for cross-resistance in mCRPC.
authors.affiliation: Department of Urology, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. Electronic address: r.vansoest@erasmusmc.nl.
authors.forename: R J
authors.initials: RJ
authors.lastname: van Soest
authors.forename: M E
authors.initials: ME
authors.lastname: van Royen
authors.forename: E S
authors.initials: ES
authors.lastname: de Morrée
authors.forename: J M
authors.initials: JM
authors.lastname: Moll
authors.forename: W
authors.initials: W
authors.lastname: Teubel
authors.forename: E A C
authors.initials: EA
authors.lastname: Wiemer
authors.forename: R H J
authors.initials: RH
authors.lastname: Mathijssen
authors.forename: R
authors.initials: R
authors.lastname: de Wit
authors.forename: W M
authors.initials: WM
authors.lastname: van Weerden
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000736:Androstenes; D000737:Androstenols / Q000494:pharmacology*; D001549:Benzamides; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D009362:Neoplasm Metastasis; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology*; D059008:Time-Lapse Imaging
chemical_list: D000736:Androstenes; D000737:Androstenols; D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; D043823:Taxoids; D049452:Green Fluorescent Proteins; D000077143:Docetaxel; D010669:Phenylthiohydantoin; C552428:cabazitaxel; C540278:enzalutamide; C089740:abiraterone
keywords: Abiraterone; Androgen receptor; Cabazitaxel; Castration-resistant prostate cancer; Docetaxel; Drug resistance; Enzalutamide