title: Loss of SLCO1B3 drives taxane resistance in prostate cancer.
abstract: Both taxanes, docetaxel and cabazitaxel, are effective treatments for metastatic castration-resistant prostate cancer (mCRPC). However, resistance to taxanes is common. Our objective was to investigate mechanisms of taxane resistance in prostate cancer.
  
  
  
  Two docetaxel-resistant patient-derived xenografts (PDXs) of CRPC were established (PC339-DOC and PC346C-DOC) in male athymic nude mice by frequent intraperitoneal administrations of docetaxel. Next-generation sequencing was performed on PDX tissue pre- and post-docetaxel resistance and gene expression profiles were compared. [(14)C]-docetaxel and [(14)C]-cabazitaxel uptake assays in vitro and cytotoxicity assays were performed to validate direct involvement of transporter genes in taxane sensitivity.
  
  
  
  Organic anion-transporting polypeptide (SLCO1B3), an influx transporter of docetaxel, was significantly downregulated in PC346C-DOC tumours. In accordance with this finding, intratumoural concentrations of docetaxel and cabazitaxel were significantly decreased in PC346C-DOC as compared with levels in chemotherapy-naive PC346C tumours. In addition, silencing of SLCO1B3 in chemo-naive PC346C resulted in a two-fold decrease in intracellular concentrations of both taxanes. Overexpression of SLCO1B3 showed higher sensitivity to docetaxel and cabazitaxel.
  
  
  
  The SLCO1B3 determines intracellular concentrations of docetaxel and cabazitaxel and consequently influences taxane efficacy. Loss of the drug transporter SLCO1B3 may drive taxane resistance in prostate cancer.
authors.affiliation: Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
authors.forename: Ellen S
authors.initials: ES
authors.lastname: de Morrée
authors.affiliation: Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.|Department of Bioinformatics, TUAS Wildau, Wildau, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Böttcher
authors.affiliation: Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: van Soest
authors.affiliation: Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Aghai
authors.affiliation: Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
authors.forename: Corrina M
authors.initials: CM
authors.lastname: de Ridder
authors.affiliation: Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, OH, USA.
authors.forename: Alice A
authors.initials: AA
authors.lastname: Gibson
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
authors.forename: Ron Hj
authors.initials: RH
authors.lastname: Mathijssen
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
authors.forename: Herman
authors.initials: H
authors.lastname: Burger
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
authors.forename: Erik Ac
authors.initials: EA
authors.lastname: Wiemer
authors.affiliation: Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, OH, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: de Wit
authors.affiliation: Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
authors.forename: Wytske M
authors.initials: WM
authors.lastname: van Weerden
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000728:Androgens; D000736:Androstenes / Q000494:pharmacology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides; D001692:Biological Transport; D045744:Cell Line, Tumor; D000077143:Docetaxel; D018432:Drug Resistance, Multiple / Q000235:genetics / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D008297:Male; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009570:Nitriles; D029362:Organic Anion Transporters, Sodium-Independent / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D043823:Taxoids / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000728:Androgens; D000736:Androstenes; D000972:Antineoplastic Agents, Phytogenic; D001549:Benzamides; D009363:Neoplasm Proteins; D009570:Nitriles; D029362:Organic Anion Transporters, Sodium-Independent; D034741:RNA, Small Interfering; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D043823:Taxoids; D000077143:Docetaxel; D010669:Phenylthiohydantoin; C552428:cabazitaxel; C540278:enzalutamide; C089740:abiraterone