ERG induces taxane resistance in castration-resistant prostate cancer

• Published in: Nature communications 2014-11, Vol.5 (1), p.5548-5548, Article 5548
• Main Authors: Galletti, Giuseppe, Matov, Alexandre, Beltran, Himisha, Fontugne, Jacqueline, Miguel Mosquera, Juan, Cheung, Cynthia, MacDonald, Theresa Y., Sung, Matthew, O’Toole, Sandra, Kench, James G., Suk Chae, Sung, Kimovski, Dragi, Tagawa, Scott T., Nanus, David M., Rubin, Mark A., Horvath, Lisa G., Giannakakou, Paraskevi, Rickman, David S.
• Format: Article
• Language: English
• Subjects: 13/2; 14; 14/19; 59; 59/5; 631/67/1059/2326; 631/67/1059/99; 631/67/589/466; 64/60; Antineoplastic Agents - administration & dosage; Cancer therapies; Cell Line, Tumor; Chemotherapy; Cohort Studies; Cooperation; Drug dosages; Drug resistance; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic - drug effects; Humanities and Social Sciences; Humans; Male; Metastasis; multidisciplinary; Oncology; Polymerization; Polymers; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - metabolism; Science; Science (multidisciplinary); Taxoids - administration & dosage; Trans-Activators - genetics; Trans-Activators - metabolism; Transcriptional Regulator ERG; Tubulin - genetics; Tubulin - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms6548

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. Metastatic castration-resistant prostate cancer is treated with the microtubule-stabilizing drugs taxanes, but resistance ultimately develops. Here Galletti et al. show that ERG, a transcription factor commonly overexpressed in prostate cancers, confers taxane resistance by binding to soluble tubulin.