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Nat Commun. 2014 Nov 25;5:5548. doi: 10.1038/ncomms6548.

ERG induces taxane resistance in castration-resistant prostate cancer.

Author information

1
Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
2
1] Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA [2] University for Information Science and Technology St Paul the Apostle, Ohrid 6000, Macedonia.
3
1] Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA [2] Institute of Precision Medicine of Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York 10065, USA.
4
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
5
1] Institute of Precision Medicine of Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York 10065, USA [2] Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
6
1] Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales 2050, Australia [2] The Kinghorn Cancer Centre / Garvan Institute of Medical Research, Victoria St, Darlinghurst, Sydney New South Wales 2010, Australia.
7
University for Information Science and Technology St Paul the Apostle, Ohrid 6000, Macedonia.
8
1] Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA [2] Weill Cornell Cancer Center, New York, New York 10065, USA.
9
1] Institute of Precision Medicine of Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York 10065, USA [2] Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065, USA [3] Weill Cornell Cancer Center, New York, New York 10065, USA.
10
1] Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales 2050, Australia [2] The Kinghorn Cancer Centre / Garvan Institute of Medical Research, Victoria St, Darlinghurst, Sydney New South Wales 2010, Australia [3] Chris O'Brien Lifehouse, Department of Medical Oncology, Royal Prince Alfred Hospital and the University of Sydney, Camperdown, Sydney New South Wales 2050, Australia.

Abstract

Taxanes are the only chemotherapies used to treat patients with metastatic castration-resistant prostate cancer (CRPC). Despite the initial efficacy of taxanes in treating CRPC, all patients ultimately fail due to the development of drug resistance. In this study, we show that ERG overexpression in in vitro and in vivo models of CRPC is associated with decreased sensitivity to taxanes. ERG affects several parameters of microtubule dynamics and inhibits effective drug-target engagement of docetaxel or cabazitaxel with tubulin. Finally, analysis of a cohort of 34 men with metastatic CRPC treated with docetaxel chemotherapy reveals that ERG-overexpressing prostate cancers have twice the chance of docetaxel resistance than ERG-negative cancers. Our data suggest that ERG plays a role beyond regulating gene expression and functions outside the nucleus to cooperate with tubulin towards taxane insensitivity. Determining ERG rearrangement status may aid in patient selection for docetaxel or cabazitaxel therapy and/or influence co-targeting approaches.

PMID:
25420520
PMCID:
PMC4244604
DOI:
10.1038/ncomms6548
[Indexed for MEDLINE]
Free PMC Article

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