ERG induces taxane resistance in castration-resistant prostate cancer

Giuseppe Galletti, Alexandre Matov, Himisha Beltran, Jacqueline Fontugne, Juan Miguel Mosquera, Cynthia Cheung, Theresa Y. MacDonald, Matthew Sung, Sandra O’Toole, James G. Kench, Sung Suk Chae, Dragi Kimovski, Scott T. Tagawa, David M. Nanus, Mark A. Rubin, Lisa G. Horvath, Paraskevi Giannakakou and David S. Rickman ()
Additional contact information
Giuseppe Galletti: Weill Cornell Medical College
Alexandre Matov: Weill Cornell Medical College
Himisha Beltran: Weill Cornell Medical College
Jacqueline Fontugne: Weill Cornell Medical College
Juan Miguel Mosquera: Institute of Precision Medicine of Weill Cornell Medical College and New York-Presbyterian Hospital
Cynthia Cheung: Weill Cornell Medical College
Theresa Y. MacDonald: Weill Cornell Medical College
Matthew Sung: Weill Cornell Medical College
Sandra O’Toole: Royal Prince Alfred Hospital, Camperdown
James G. Kench: Royal Prince Alfred Hospital, Camperdown
Sung Suk Chae: Weill Cornell Medical College
Dragi Kimovski: University for Information Science and Technology St Paul the Apostle
Scott T. Tagawa: Weill Cornell Medical College
David M. Nanus: Weill Cornell Medical College
Mark A. Rubin: Institute of Precision Medicine of Weill Cornell Medical College and New York-Presbyterian Hospital
Lisa G. Horvath: Royal Prince Alfred Hospital, Camperdown
Paraskevi Giannakakou: Weill Cornell Medical College
David S. Rickman: Institute of Precision Medicine of Weill Cornell Medical College and New York-Presbyterian Hospital

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6548

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