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

共 50 条

[11] Targeting Cancer Stem Cells in Castration-Resistant Prostate Cancer
Yun, Eun-Jin
Zhou, Jiancheng
Lin, Chun-Jung
Hernandez, Elizabeth
Fazli, Ladan
Gleave, Martin
Hsieh, Jer-Tsong
CLINICAL CANCER RESEARCH, 2016, 22 (03) : 670 - 679
[12] Targeting extra-gonadal androgens in castration-resistant prostate cancer
Grist, Emily
de Bono, Johann S.
Attard, Gerhardt
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, 2015, 145 : 157 - 163
[13] Metastatic castration-resistant prostate cancer
Henriques, Vanessa
Wenzel, Mike
Demes, Melanie-Christin
Koellermann, Jens
PATHOLOGE, 2021, 42 (04): : 431 - 438
[14] Targeting NPRL2 to enhance the efficacy of Olaparib in castration-resistant prostate cancer
Chen, Xin
Chen, Zhixiong
Zheng, Bin
Tang, Wei
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2019, 508 (02) : 620 - 625
[15] Mechanisms of acquired resistance to androgen receptor targeting drugs in castration-resistant prostate cancer
Chism, David D.
De Silva, Dinuka
Whang, Young E.
EXPERT REVIEW OF ANTICANCER THERAPY, 2014, 14 (11) : 1369 - 1378
[16] Targeting Galectin-1 Impairs Castration-Resistant Prostate Cancer Progression and Invasion
Shih, Tsung-Chieh
Liu, Ruiwu
Wu, Chun-Te
Li, Xiaocen
Xiao, Wenwu
Deng, Xiaojun
Kiss, Sophie
Wang, Ting
Chen, Xiao-Jia
Carney, Randy
Kung, Hsing-Jien
Duan, Yong
Ghosh, Paramita M.
Lam, Kit S.
CLINICAL CANCER RESEARCH, 2018, 24 (17) : 4319 - 4331
[17] Targeting mTOR Complex 2 in Castration-Resistant Prostate Cancer with Acquired Docetaxel Resistance
Huang, Yujie
Zhai, You
Wu, Meijia
Chang, Chengdong
Luo, Jindan
Hong, Dongsheng
Zhao, Qingwei
Dai, Yao
Liu, Jian
DRUG DESIGN DEVELOPMENT AND THERAPY, 2022, 16 : 3817 - 3828
[18] Enzalutamide for the treatment of metastatic castration-resistant prostate cancer
Rodriguez-Vida, Alejo
Galazi, Myria
Rudman, Sarah
Chowdhury, Simon
Sternberg, Cora N.
DRUG DESIGN DEVELOPMENT AND THERAPY, 2015, 9 : 3325 - 3339
[19] TARGETING HSP 27 FOR THE TREATMENT OF CASTRATION-RESISTANT PROSTATE CANCER
Zoubeidi, A.
Chi, K. N.
Gleave, M.
DRUGS OF THE FUTURE, 2011, 36 (03) : 241 - 247
[20] Androgen Receptor Antagonists in Castration-Resistant Prostate Cancer
Rathkopf, Dana
Scher, Howard I.
CANCER JOURNAL, 2013, 19 (01) : 43 - 49

← 1 2 3 4 5 →