Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer

被引：469

作者：

Shu, Shaokun ^{[1
,2
,3
]}

Lin, Charles Y. ^{[1
,2
,3
]}

He, Housheng Hansen ^{[1
,2
,3
,4
,5
,6
,7
]}

Witwicki, Robert M. ^{[1
,2
,3
]}

Tabassum, Doris P. ^{[1
]}

Roberts, Justin M. ^{[1
]}

Janiszewska, Michalina ^{[1
,2
,3
]}

Huh, Sung Jin ^{[1
,2
,3
]}

Liang, Yi ^{[6
]}

Ryan, Jeremy ^{[1
,2
,3
]}

Doherty, Ernest ^{[1
,8
]}

Mohammed, Hisham ^{[9
]}

Guo, Hao ^{[4
,5
]}

Stover, Daniel G. ^{[1
,2
,3
]}

Ekram, Muhammad B. ^{[1
,2
,3
]}

Peluffo, Guillermo ^{[1
,2
,3
]}

Brown, Jonathan ^{[1
,2
,3
]}

D'Santos, Clive ^{[9
]}

Krop, Ian E. ^{[1
,2
,3
]}

Dillon, Deborah ^{[1
,10
,11
]}

McKeown, Michael ^{[1
,2
,3
]}

Ott, Christopher ^{[1
,2
,3
]}

Qi, Jun ^{[1
,2
,3
]}

Ni, Min ^{[1
,2
,3
]}

Rao, Prakash K. ^{[12
]}

Duarte, Melissa ^{[12
]}

Wu, Shwu-Yuan ^{[13
,14
]}

Chiang, Cheng-Ming ^{[13
,14
]}

Anders, Lars ^{[15
]}

Young, Richard A. ^{[15
]}

Winer, Eric P. ^{[1
,2
,3
]}

Letai, Antony ^{[1
,2
,3
]}

Barry, William T. ^{[2
,3
,4
,5
]}

Carroll, Jason S. ^{[9
]}

Long, Henry W. ^{[1
,12
]}

Brown, Myles ^{[1
,2
,3
,12
]}

Liu, X. Shirley ^{[4
,5
,12
,16
]}

Meyer, Clifford A. ^{[4
,5
]}

Bradner, James E. ^{[1
,2
,3
,16
]}

Polyak, Kornelia ^{[1
,2
,3
,12
,16
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[2] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[4] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA

[5] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA

[6] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 1L7, Canada

[7] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2M9, Canada

[8] Harvard Univ, Cambridge, MA 02138 USA

[9] Univ Cambridge, Cambridge Inst, Canc Res UK, Cambridge CB2 0RE, England

[10] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[11] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

[12] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA

[13] Univ Texas SW Med Ctr Dallas, Simmons Comprehens Canc Ctr, Dept Biochem, Dallas, TX 75390 USA

[14] Univ Texas SW Med Ctr Dallas, Simmons Comprehens Canc Ctr, Dept Pharmacol, Dallas, TX 75390 USA

[15] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

[16] Broad Inst, Cambridge, MA 02142 USA

来源：

NATURE | 2016年 / 529卷 / 7586期

基金：

加拿大自然科学与工程研究理事会; 加拿大创新基金会;

关键词：

SUPER-ENHANCERS; SELECTIVE-INHIBITION; CELL IDENTITY; RNA-SEQ; C-MYC; INFLAMMATION; STRATEGY; LEUKEMIA; SUBTYPES; PP2A;

D O I：

10.1038/nature16508

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：

Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy(1-3). BET bromodomain inhibitors, which have shown efficacy in several models of cancer(4-6), have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs(7-9). Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance.

引用

页码：413 / +

页数：24

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[1] Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer
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