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BET bromodomain inhibitors synergize with ATR inhibitors to induce DNA damage, apoptosis, senescence-associated secretory pathway and ER stress in Myc-induced lymphoma cells.

Journal article
Authors Somsundar Veppil Muralidharan
Joydeep Bhadury
Lisa M Nilsson
Lydia C. Green
K G McLure
Jonas A Nilsson
Published in Oncogene
Volume 35
Pages 4689–4697
ISSN 1476-5594
Publication year 2016
Published at Institute of Clinical Sciences, Department of Surgery
Pages 4689–4697
Language en
Links dx.doi.org/10.1038/onc.2015.521
Subject categories Cancer and Oncology, Surgery

Abstract

Inhibiting the bromodomain and extra-terminal (BET) domain family of epigenetic reader proteins has been shown to have potent anti-tumoral activity, which is commonly attributed to suppression of transcription. In this study, we show that two structurally distinct BET inhibitors (BETi) interfere with replication and cell cycle progression of murine Myc-induced lymphoma cells at sub-lethal concentrations when the transcriptome remains largely unaltered. This inhibition of replication coincides with a DNA-damage response and enhanced sensitivity to inhibitors of the upstream replication stress sensor ATR in vitro and in mouse models of B-cell lymphoma. Mechanistically, ATR and BETi combination therapy cause robust transcriptional changes of genes involved in cell death, senescence-associated secretory pathway, NFkB signaling and ER stress. Our data reveal that BETi can potentiate the cell stress and death caused by ATR inhibitors. This suggests that ATRi can be used in combination therapies of lymphomas without the use of genotoxic drugs.Oncogene advance online publication, 25 January 2016; doi:10.1038/onc.2015.521.

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