ERG induces taxane resistance in castration-resistant prostate cancer

被引：98

作者：

Galletti, Giuseppe ^{[1
]}

Matov, Alexandre ^{[1
,2
]}

Beltran, Himisha ^{[1
,3
,4
]}

Fontugne, Jacqueline ^{[5
]}

Mosquera, Juan Miguel ^{[3
,4
,5
]}

Cheung, Cynthia ^{[5
]}

MacDonald, Theresa Y. ^{[5
]}

Sung, Matthew ^{[1
]}

O'Toole, Sandra ^{[6
,7
]}

Kench, James G. ^{[6
,7
]}

Chae, Sung Suk ^{[5
]}

Kimovski, Dragi ^{[2
]}

Tagawa, Scott T. ^{[1
,8
]}

Nanus, David M. ^{[1
,8
]}

Rubin, Mark A. ^{[3
,4
,5
,8
]}

Horvath, Lisa G. ^{[6
,7
,9
,10
]}

Giannakakou, Paraskevi ^{[1
,8
]}

Rickman, David S. ^{[3
,4
,5
,8
]}

机构：

[1] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA

[2] Univ Informat Sci & Technol St Paul Apostle, Ohrid 6000, Macedonia

[3] Weill Cornell Med Coll, Inst Precis Med, New York, NY 10065 USA

[4] New York Presbyterian Hosp, New York, NY 10065 USA

[5] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10065 USA

[6] Royal Prince Alfred Hosp, Dept Tissue Pathol & Diagnost Oncol, Sydney, NSW 2050, Australia

[7] Kinghorn Canc Ctr, Garvan Inst Med Res, Sydney, NSW 2010, Australia

[8] Weill Cornell Canc Ctr, New York, NY 10065 USA

[9] Royal Prince Alfred Hosp, Dept Med Oncol, Chris OBrien Lifehouse, Sydney, NSW 2050, Australia

[10] Univ Sydney, Sydney, NSW 2050, Australia

来源：

NATURE COMMUNICATIONS | 2014年 / 5卷

关键词：

CIRCULATING TUMOR-CELLS; PLUS-END TRACKING; ANDROGEN RECEPTOR; TRANSCRIPTION FACTORS; MICROTUBULE CYTOSKELETON; NUCLEAR ACCUMULATION; DYNAMIC INSTABILITY; TUBULIN; FUSION; TMPRSS2-ERG;

D O I：

10.1038/ncomms6548

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：12

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