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Loss of SLCO1B3 drives taxane resistance in prostate cancer

BACKGROUND: 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. METHODS: Two docetaxel-resistant p...

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Autores principales: de Morrée, Ellen S, Böttcher, René, van Soest, Robert J, Aghai, Ashraf, de Ridder, Corrina M, Gibson, Alice A, Mathijssen, Ron HJ, Burger, Herman, Wiemer, Erik AC, Sparreboom, Alex, de Wit, Ronald, van Weerden, Wytske M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023781/
https://www.ncbi.nlm.nih.gov/pubmed/27537383
http://dx.doi.org/10.1038/bjc.2016.251
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author de Morrée, Ellen S
Böttcher, René
van Soest, Robert J
Aghai, Ashraf
de Ridder, Corrina M
Gibson, Alice A
Mathijssen, Ron HJ
Burger, Herman
Wiemer, Erik AC
Sparreboom, Alex
de Wit, Ronald
van Weerden, Wytske M
author_facet de Morrée, Ellen S
Böttcher, René
van Soest, Robert J
Aghai, Ashraf
de Ridder, Corrina M
Gibson, Alice A
Mathijssen, Ron HJ
Burger, Herman
Wiemer, Erik AC
Sparreboom, Alex
de Wit, Ronald
van Weerden, Wytske M
author_sort de Morrée, Ellen S
collection PubMed
description BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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spelling pubmed-50237812017-09-06 Loss of SLCO1B3 drives taxane resistance in prostate cancer de Morrée, Ellen S Böttcher, René van Soest, Robert J Aghai, Ashraf de Ridder, Corrina M Gibson, Alice A Mathijssen, Ron HJ Burger, Herman Wiemer, Erik AC Sparreboom, Alex de Wit, Ronald van Weerden, Wytske M Br J Cancer Translational Therapeutics BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. Nature Publishing Group 2016-09-06 2016-08-18 /pmc/articles/PMC5023781/ /pubmed/27537383 http://dx.doi.org/10.1038/bjc.2016.251 Text en Copyright © 2016 Cancer Research UK http://creativecommons.org/licenses/by-nc-sa/4.0/ From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
spellingShingle Translational Therapeutics
de Morrée, Ellen S
Böttcher, René
van Soest, Robert J
Aghai, Ashraf
de Ridder, Corrina M
Gibson, Alice A
Mathijssen, Ron HJ
Burger, Herman
Wiemer, Erik AC
Sparreboom, Alex
de Wit, Ronald
van Weerden, Wytske M
Loss of SLCO1B3 drives taxane resistance in prostate cancer
title Loss of SLCO1B3 drives taxane resistance in prostate cancer
title_full Loss of SLCO1B3 drives taxane resistance in prostate cancer
title_fullStr Loss of SLCO1B3 drives taxane resistance in prostate cancer
title_full_unstemmed Loss of SLCO1B3 drives taxane resistance in prostate cancer
title_short Loss of SLCO1B3 drives taxane resistance in prostate cancer
title_sort loss of slco1b3 drives taxane resistance in prostate cancer
topic Translational Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023781/
https://www.ncbi.nlm.nih.gov/pubmed/27537383
http://dx.doi.org/10.1038/bjc.2016.251
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