title: Blockade of oncogenic IκB kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors.
abstract: In the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), NF-κB activity is essential for viability of the malignant cells and is sustained by constitutive activity of IκB kinase (IKK) in the cytoplasm. Here, we report an unexpected role for the bromodomain and extraterminal domain (BET) proteins BRD2 and BRD4 in maintaining oncogenic IKK activity in ABC DLBCL. IKK activity was reduced by small molecules targeting BET proteins as well as by genetic knockdown of BRD2 and BRD4 expression, thereby inhibiting downstream NF-κB-driven transcriptional programs and killing ABC DLBCL cells. Using a high-throughput platform to screen for drug-drug synergy, we observed that the BET inhibitor JQ1 combined favorably with multiple drugs targeting B-cell receptor signaling, one pathway that activates IKK in ABC DLBCL. The BTK kinase inhibitor ibrutinib, which is in clinical development for the treatment of ABC DLBCL, synergized strongly with BET inhibitors in killing ABC DLBCL cells in vitro and in a xenograft mouse model. These findings provide a mechanistic basis for the clinical development of BET protein inhibitors in ABC DLBCL, particularly in combination with other modulators of oncogenic IKK signaling.
authors: Lymphoid Malignancies Branch and.
authors: Michele
authors: M
authors: Ceribelli
authors: Lymphoid Malignancies Branch and.
authors: Priscilla N
authors: PN
authors: Kelly
authors: Lymphoid Malignancies Branch and.
authors: Arthur L
authors: AL
authors: Shaffer
authors: Biometric Research Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors: George W
authors: GW
authors: Wright
authors: Lymphoid Malignancies Branch and.
authors: Wenming
authors: W
authors: Xiao
authors: Lymphoid Malignancies Branch and.
authors: Yibin
authors: Y
authors: Yang
authors: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892; and.
authors: Lesley A
authors: LA
authors: Mathews Griner
authors: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892; and.
authors: Rajarshi
authors: R
authors: Guha
authors: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892; and.
authors: Paul
authors: P
authors: Shinn
authors: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892; and.
authors: Jonathan M
authors: JM
authors: Keller
authors: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892; and.
authors: Dongbo
authors: D
authors: Liu
authors: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892; and.
authors: Paresma R
authors: PR
authors: Patel
authors: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892; and.
authors: Marc
authors: M
authors: Ferrer
authors: Constellation Pharmaceuticals, Inc., Cambridge, MA 02142.
authors: Shivangi
authors: S
authors: Joshi
authors: Constellation Pharmaceuticals, Inc., Cambridge, MA 02142.
authors: Sujata
authors: S
authors: Nerle
authors: Constellation Pharmaceuticals, Inc., Cambridge, MA 02142.
authors: Peter
authors: P
authors: Sandy
authors: Constellation Pharmaceuticals, Inc., Cambridge, MA 02142.
authors: Emmanuel
authors: E
authors: Normant
authors: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892; and.
authors: Craig J
authors: CJ
authors: Thomas
authors: Lymphoid Malignancies Branch and lstaudt@mail.nih.gov.
authors: Louis M
authors: LM
authors: Staudt
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000818:Animals; D001381:Azepines / Q000494:pharmacology / Q000633:toxicity; D018797:Cell Cycle Proteins; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival; D004357:Drug Synergism; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology / Q000633:toxicity; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D000225:Adenine; D001381:Azepines; D018797:Cell Cycle Proteins; D051550:I-kappa B Kinase; D009687:Nuclear Proteins; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D011743:Pyrimidines; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C441289:BRD4 protein, human; C551803:ibrutinib
keywords: cancer therapy; drug synergism