Targeting the MLL complex in castration-resistant prostate cancer

被引：152

作者：

Malik, Rohit ^{[1
,2
]}

Khan, Amjad P. ^{[1
,2
]}

Asangani, Irfan A. ^{[1
,2
]}

Cieslik, Marcin ^{[1
,2
]}

Prensner, John R. ^{[1
,2
]}

Wang, Xiaoju ^{[1
,2
]}

Iyer, Matthew K. ^{[1
,2
]}

Jiang, Xia ^{[1
,2
]}

Borkin, Dmitry ^{[2
]}

Escara-Wilke, June ^{[1
,2
]}

Stender, Rachell ^{[1
,2
]}

Wu, Yi-Mi ^{[1
,2
]}

Niknafs, Yashar S. ^{[1
]}

Jing, Xiaojun ^{[1
,2
]}

Qiao, Yuanyuan ^{[1
,2
]}

Palanisamy, Nallasivam ^{[1
,2
,3
]}

Kunju, Lakshmi P. ^{[1
,2
,4
]}

Krishnamurthy, Pranathi M. ^{[1
]}

Yocum, Anastasia K. ^{[1
]}

Mellacheruvu, Dattatreya ^{[2
,5
]}

Nesvizhskii, Alexey I. ^{[1
,2
,5
]}

Cao, Xuhong ^{[1
,6
]}

Dhanasekaran, Saravana M. ^{[1
,2
]}

Feng, Felix Y. ^{[1
,7
,8
]}

Grembecka, Jolanta ^{[2
]}

Cierpicki, Tomasz ^{[2
]}

Chinnaiyan, Arul M. ^{[1
,2
,4
,5
,6
,8
]}

机构：

[1] Univ Michigan, Michigan Ctr Translat Pathol, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA

[3] Henry Ford Hlth Syst, Dept Urol, Detroit, MI USA

[4] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA

[5] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA

[6] Univ Michigan, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA

[7] Univ Michigan, Radiat Oncol, Ann Arbor, MI 48109 USA

[8] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA

来源：

NATURE MEDICINE | 2015年 / 21卷 / 04期

基金：

美国国家卫生研究院;

关键词：

ANDROGEN-RECEPTOR; INCREASED SURVIVAL; MENIN; GENE; EXPRESSION; PROTEINS; ANTIANDROGEN; CELLS;

D O I：

10.1038/nm.3830

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castrationresistant prostate cancer (CRPC). Although prior work has focused on targeting AR directly, co-activators of AR signaling, which may represent new therapeutic targets, are relatively underexplored. Here we demonstrate that the mixed-lineage leukemia protein (MLL) complex, a well-known driver of MLL fusion-positive leukemia, acts as a co-activator of AR signaling. AR directly interacts with the MLL complex via the menin-MLL subunit. Menin expression is higher in CRPC than in both hormone-naive prostate cancer and benign prostate tissue, and high menin expression correlates with poor overall survival of individuals diagnosed with prostate cancer. Treatment with a small-molecule inhibitor of menin-MLL interaction blocks AR signaling and inhibits the growth of castration-resistant tumors in vivo in mice. Taken together, this work identifies the MLL complex as a crucial co-activator of AR and a potential therapeutic target in advanced prostate cancer.

引用

页码：344 / +

页数：11

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