title: BET bromodomain inhibitors synergize with ATR inhibitors to induce DNA damage, apoptosis, senescence-associated secretory pathway and ER stress in Myc-induced lymphoma cells.
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.
authors.affiliation: Department of Surgery, Sahlgrenska Cancer Center, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: S V
authors.initials: SV
authors.lastname: Muralidharan
authors.affiliation: Department of Surgery, Sahlgrenska Cancer Center, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: J
authors.identifier: 0000-0002-4333-9974
authors.initials: J
authors.lastname: Bhadury
authors.affiliation: Department of Surgery, Sahlgrenska Cancer Center, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: L M
authors.initials: LM
authors.lastname: Nilsson
authors.affiliation: Department of Surgery, Sahlgrenska Cancer Center, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: L C
authors.initials: LC
authors.lastname: Green
authors.affiliation: Zenith Epigenetics Corp, Calgary, Alberta, Canada.
authors.forename: K G
authors.initials: KG
authors.lastname: McLure
authors.affiliation: Department of Surgery, Sahlgrenska Cancer Center, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: J A
authors.initials: JA
authors.lastname: Nilsson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051548:Histone Acetyltransferases; D056488:Histone Chaperones; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000008:administration & dosage*; D000092468:Bromodomain Containing Proteins
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D051548:Histone Acetyltransferases; D056488:Histone Chaperones; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D054852:Small Molecule Libraries; C489427:MYC protein, human; C402649:BRD1 protein, human; D000092468:Bromodomain Containing Proteins; C576597:ATR protein, human