An in-tumor genetic screen reveals that the BET bromodomain protein, BRD4, is a potential therapeutic target in ovarian carcinoma

被引：145

作者：

Baratta, Maria Giuseppina ^{[1
,4
]}

Schinzel, Anna C. ^{[2
,4
,5
]}

Zwang, Yaara ^{[2
,4
,5
]}

Bandopadhayay, Pratiti ^{[1
,4
,5
]}

Bowman-Colin, Christian ^{[1
,4
]}

Kutt, Jennifer ^{[1
]}

Curtis, Jennifer ^{[1
]}

Piao, Huiying ^{[1
]}

Wong, Laura C. ^{[1
]}

Kung, Andrew L. ^{[3
,4
]}

Beroukhim, Rameen ^{[1
,2
,4
,5
]}

Bradner, James E. ^{[1
,2
,4
,5
]}

Drapkin, Ronny ^{[2
,4
]}

Hahn, William C. ^{[2
,4
,5
]}

Liu, Joyce F. ^{[2
,4
]}

Livingston, David M. ^{[1
,4
]}

机构：

[1] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[2] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Boston, MA 02115 USA

[5] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2015年 / 112卷 / 01期

基金：

美国国家卫生研究院;

关键词：

ovarian cancer; in vivo screen; targeted therapy; BRD4; MYCN; CREATINE-KINASE-B; SELECTIVE-INHIBITION; SEROUS CARCINOMA; HUMAN CANCERS; EXPRESSION; MYC; RECRUITMENT; CHROMATIN; LEUKEMIA; CELLS;

D O I：

10.1073/pnas.1422165112

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：

High-grade serous ovarian carcinoma (HGSOC) is the most common and aggressive form of epithelial ovarian cancer, for which few targeted therapies exist. To search for new therapeutic target proteins, we performed an in vivo shRNA screen using an established human HGSOC cell line growing either subcutaneously or intraperitoneally in immunocompromised mice. We identified genes previously implicated in ovarian cancer such as AURKA1, ERBB3, CDK2, and mTOR, as well as several novel candidates including BRD4, VRK1, and GALK2. We confirmed, using both genetic and pharmacologic approaches, that the activity of BRD4, an epigenetic transcription modulator, is necessary for proliferation/survival of both an established human ovarian cancer cell line (OVCAR8) and a subset of primary serous ovarian cancer cell strains (DFs). Among the DFs tested, the strains sensitive to BRD4 inhibition revealed elevated expression of either MYCN or c-MYC, with MYCN expression correlating closely with JQ1 sensitivity. Accordingly, primary human xenografts derived from high-MYCN or c-MYC strains exhibited sensitivity to BRD4 inhibition. These data suggest that BRD4 inhibition represents a new therapeutic approach for MYC-overexpressing HGSOCs.

引用

页码：232 / 237

页数：6

共 37 条

[1] Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary [J].

Ahmed, Ashour Ahmed ;

Etemadmoghadam, Dariush ;

Temple, Jillian ;

Lynch, Andy G. ;

Riad, Mohamed ;

Sharma, Raghwa ;

Stewart, Colin ;

Fereday, Sian ;

Caldas, Carlos ;

DeFazio, Anna ;

Bowtell, David ;

Brenton, James D. .

JOURNAL OF PATHOLOGY, 2010, 221 (01) :49-56

[2] Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer [J].

Asangani, Irfan A. ;

Dommeti, Vijaya L. ;

Wang, Xiaoju ;

Malik, Rohit ;

Cieslik, Marcin ;

Yang, Rendong ;

Escara-Wilke, June ;

Wilder-Romans, Kari ;

Dhanireddy, Sudheer ;

Engelke, Carl ;

Iyer, Mathew K. ;

Jing, Xiaojun ;

Wu, Yi-Mi ;

Cao, Xuhong ;

Qin, Zhaohui S. ;

Wang, Shaomeng ;

Feng, Felix Y. ;

Chinnaiyan, Arul M. .

NATURE, 2014, 510 (7504) :278-+

[3]

Atsumi T, 2002, CANCER RES, V62, P5881

[4] BET Bromodomain Inhibition of MYC-Amplified Medulloblastoma [J].

Bandopadhayay, Pratiti ;

Bergthold, Guillaume ;

Nguyen, Brian ;

Schubert, Simone ;

Gholamin, Sharareh ;

Tang, Yujie ;

Bolin, Sara ;

Schumacher, Steven E. ;

Zeid, Rhamy ;

Masoud, Sabran ;

Yu, Furong ;

Vue, Nujsaubnusi ;

Gibson, William J. ;

Paolella, Brenton R. ;

Mitra, Siddhartha S. ;

Cheshier, Samuel H. ;

Qi, Jun ;

Liu, Kun-Wei ;

Wechsler-Reya, Robert ;

Weiss, William A. ;

Swartling, Fredrik J. ;

Kieran, Mark W. ;

Bradner, James E. ;

Beroukhim, Rameen ;

Cho, Yoon-Jae .

CLINICAL CANCER RESEARCH, 2014, 20 (04) :912-925

[5] Integrated genomic analyses of ovarian carcinoma [J].

Bell, D. ;

Berchuck, A. ;

Birrer, M. ;

Chien, J. ;

Cramer, D. W. ;

Dao, F. ;

Dhir, R. ;

DiSaia, P. ;

Gabra, H. ;

Glenn, P. ;

Godwin, A. K. ;

Gross, J. ;

Hartmann, L. ;

Huang, M. ;

Huntsman, D. G. ;

Iacocca, M. ;

Imielinski, M. ;

Kalloger, S. ;

Karlan, B. Y. ;

Levine, D. A. ;

Mills, G. B. ;

Morrison, C. ;

Mutch, D. ;

Olvera, N. ;

Orsulic, S. ;

Park, K. ;

Petrelli, N. ;

Rabeno, B. ;

Rader, J. S. ;

Sikic, B. I. ;

Smith-McCune, K. ;

Sood, A. K. ;

Bowtell, D. ;

Penny, R. ;

Testa, J. R. ;

Chang, K. ;

Dinh, H. H. ;

Drummond, J. A. ;

Fowler, G. ;

Gunaratne, P. ;

Hawes, A. C. ;

Kovar, C. L. ;

Lewis, L. R. ;

Morgan, M. B. ;

Newsham, I. F. ;

Santibanez, J. ;

Reid, J. G. ;

Trevino, L. R. ;

Wu, Y. -Q. ;

Wang, M. .

NATURE, 2011, 474 (7353) :609-615

[6] The genesis and evolution of high-grade serous ovarian cancer [J].

Bowtell, David D. L. .

NATURE REVIEWS CANCER, 2010, 10 (11) :803-808

[7] Emerging landscape of oncogenic signatures across human cancers [J].

Ciriello, Giovanni ;

Miller, Martin L. ;

Aksoy, Buelent Arman ;

Senbabaoglu, Yasin ;

Schultz, Nikolaus ;

Sander, Chris .

NATURE GENETICS, 2013, 45 (10) :1127-U247

[8] Inhibition of FGFR2 and FGFR1 increases cisplatin sensitivity in ovarian cancer [J].

Cole, Claire ;

Lau, Sin ;

Backen, Alison ;

Clamp, Andrew ;

Rushton, Graham ;

Dive, Caroline ;

Hodgkinson, Cassandra ;

McVey, Rhona ;

Kitchener, Henry ;

Jayson, Gordon C. .

CANCER BIOLOGY & THERAPY, 2010, 10 (05) :495-504

[9] Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia [J].

Dawson, Mark A. ;

Prinjha, Rab K. ;

Dittmann, Antje ;

Giotopoulos, George ;

Bantscheff, Marcus ;

Chan, Wai-In ;

Robson, Samuel C. ;

Chung, Chun-wa ;

Hopf, Carsten ;

Savitski, Mikhail M. ;

Huthmacher, Carola ;

Gudgin, Emma ;

Lugo, Dave ;

Beinke, Soren ;

Chapman, Trevor D. ;

Roberts, Emma J. ;

Soden, Peter E. ;

Auger, Kurt R. ;

Mirguet, Olivier ;

Doehner, Konstanze ;

Delwel, Ruud ;

Burnett, Alan K. ;

Jeffrey, Phillip ;

Drewes, Gerard ;

Lee, Kevin ;

Huntly, Brian J. P. ;

Kouzarides, Tony .

NATURE, 2011, 478 (7370) :529-533

[10] BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc [J].

Delmore, Jake E. ;

Issa, Ghayas C. ;

Lemieux, Madeleine E. ;

Rahl, Peter B. ;

Shi, Junwei ;

Jacobs, Hannah M. ;

Kastritis, Efstathios ;

Gilpatrick, Timothy ;

Paranal, Ronald M. ;

Qi, Jun ;

Chesi, Marta ;

Schinzel, Anna C. ;

McKeown, Michael R. ;

Heffernan, Timothy P. ;

Vakoc, Christopher R. ;

Bergsagel, P. Leif ;

Ghobrial, Irene M. ;

Richardson, Paul G. ;

Young, Richard A. ;

Hahn, William C. ;

Anderson, Kenneth C. ;

Kung, Andrew L. ;

Bradner, James E. ;

Mitsiades, Constantine S. .

CELL, 2011, 146 (06) :903-916

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