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- Title
Loss of SLCO1B3 drives taxane resistance in prostate cancer.
- Authors
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; de Morrée, Ellen S; Böttcher, René
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Publication
British Journal of Cancer, 2016, Vol 115, Issue 6, p674
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/bjc.2016.251