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

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

  • Oncogene. 2016 Sep 8;35(36):4689-97. doi: 10.1038/onc.2015.521.
S V Muralidharan 1 J Bhadury 1 L M Nilsson 1 L C Green 1 K G McLure 2 J A Nilsson 1
Affiliations

Affiliations

  • 1 Department of Surgery, Sahlgrenska Cancer Center, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
  • 2 Zenith Epigenetics Corp, Calgary, Alberta, Canada.
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.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-14731
    98.32%, ATR Inhibitor