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Nature. 2015 Sep 24;525(7570):538-42. doi: 10.1038/nature14888. Epub 2015 Sep 14.

BET inhibitor resistance emerges from leukaemia stem cells.

Author information

1
Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
2
Sir Peter MacCallum Department of Oncology, The University of Melbourne, East Melbourne, Victoria 3002, Australia.
3
Department of Haematology, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
4
Bioinformatics Division, The Walter &Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
5
Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
6
Department of Haematology, Cambridge Institute for Medical Research and Wellcome Trust-MRC Stem Cell Institute, Cambridge CB2 0XY, UK.
7
Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK.
8
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
9
Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA.
10
QIMR Berghofer Medical Research Institute, University of Queensland, Brisbane, Queensland 4029, Australia.
11
Gurdon Institute and Department of Pathology, Tennis Court Road, Cambridge CB2 1QN, UK.

Abstract

Bromodomain and extra terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a new therapeutic opportunity by directly targeting bromodomain proteins that bind acetylated chromatin marks. Early clinical trials have shown promise, especially in acute myeloid leukaemia, and therefore the evaluation of resistance mechanisms is 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 not mediated 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 increased Wnt/β-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.

PMID:
26367796
PMCID:
PMC6069604
DOI:
10.1038/nature14888
[Indexed for MEDLINE]
Free PMC Article

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