BET inhibitor resistance emerges from leukaemia stem cells

被引：439

作者：

Fong, Chun Yew ^{[1
,2
,3
]}

Gilan, Omer ^{[1
,2
]}

Lam, Enid Y. N. ^{[1
]}

Rubin, Alan F. ^{[4
,5
]}

Ftouni, Sarah ^{[1
]}

Tyler, Dean ^{[1
,2
]}

Stanley, Kym ^{[1
]}

Sinha, Devbarna ^{[1
]}

Yeh, Paul ^{[1
,2
,3
]}

Morison, Jessica ^{[6
,7
]}

Giotopoulos, George ^{[6
,7
]}

Lugo, Dave ^{[8
]}

Jeffrey, Philip ^{[8
]}

Lee, Stanley Chun-Wei ^{[9
]}

Carpenter, Christopher ^{[10
]}

Gregory, Richard ^{[8
]}

Ramsay, Robert G. ^{[1
,2
]}

Lane, Steven W. ^{[11
]}

Abdel-Wahab, Omar ^{[9
]}

Kouzarides, Tony ^{[12
,13
]}

Johnstone, Ricky W. ^{[1
,2
]}

Dawson, Sarah-Jane ^{[1
,2
]}

Huntly, Brian J. P. ^{[6
,7
]}

Prinjha, Rab K. ^{[8
]}

Papenfuss, Anthony T. ^{[1
,2
,4
,5
]}

Dawson, Mark A. ^{[1
,2
,3
]}

机构：

[1] Peter MacCallum Canc Ctr, Canc Res Div, East Melbourne, Vic 3002, Australia

[2] Univ Melbourne, Sir Peter MacCallum Dept Oncol, East Melbourne, Vic 3002, Australia

[3] Peter MacCallum Canc Ctr, Dept Haematol, East Melbourne, Vic 3002, Australia

[4] Walter & Eliza Hall Inst Med Res, Bioinformat Div, Parkville, Vic 3052, Australia

[5] Univ Melbourne, Dept Med Biol, Parkville, Vic 3010, Australia

[6] Cambridge Inst Med Res, Dept Haematol, Cambridge CB2 OXY, England

[7] Wellcome Trust MRC Stem Cell Inst, Cambridge CB2 0XY, England

[8] GlaxoSmithKline, Epinova DPU, Immunoinflammat Ctr Excellence Drug Discovery, Med Res Ctr, Stevenage SG1 2NY, Herts, England

[9] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[10] GlaxoSmithKline, Canc Epigenet DPU, Oncol R&D, Collegeville, PA 19426 USA

[11] Univ Queensland, QIMR Berghofer Med Res Inst, Brisbane, Qld 4029, Australia

[12] Gurdon Inst, Cambridge CB2 1QN, England

[13] Dept Pathol, Cambridge CB2 1QN, England

来源：

NATURE | 2015年 / 525卷 / 7570期

关键词：

SELECTIVE-INHIBITION; DRUG-RESISTANCE; CANCER; MUTATIONS; MECHANISM; DISCOVERY; CHROMATIN; ACCURATE; PROGRAM;

D O I：

10.1038/nature14888

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：

Bromodomain and extra terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a newtherapeutic opportunity by directly targeting bromodomain proteins that bind acetylated chromatin marks(1,2). Early clinical trials have shown promise, especially in acute myeloid leukaemia(3), and therefore the evaluation of resistance mechanismsis crucial to optimize the clinical efficacy of these drugs. Here we use primary mouse haematopoietic stem and progenitor cells immortalized with the fusion protein MLL-AF9 to generate several single-cell clones that demonstrate resistance, in vitro and in vivo, to the prototypical BET inhibitor, I-BET. Resistance to I-BET confers cross-resistance to chemically distinct BET inhibitors such as JQ1, as well as resistance to genetic knockdown of BET proteins. Resistance is notmediated through increased drug efflux or metabolism, but is shown to emerge from leukaemia stem cells both ex vivo and in vivo. Chromatin-bound BRD4 is globally reduced in resistant cells, whereas the expression of key target genes such as Myc remains unaltered, highlighting the existence of alternative mechanisms to regulate transcription. We demonstrate that resistance to BET inhibitors, in human and mouse leukaemia cells, is in part a consequence of increasedWnt/beta-catenin signalling, and negative regulation of this pathway results in restoration of sensitivity to I-BET in vitro and in vivo. Together, these findings provide new insights into the biology of acute myeloid leukaemia, highlight potential therapeutic limitations of BET inhibitors, and identify strategies that may enhance the clinical utility of these unique targeted therapies.

引用

页码：538 / +

页数：19

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