title: Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib.
abstract: Mantle cell lymphoma (MCL) cells exhibit increased B-cell receptor and nuclear factor (NF)-κB activities. The bromodomain and extra-terminal (BET) protein bromodomain 4 is essential for the transcriptional activity of NF-κB. Here, we demonstrate that treatment with the BET protein bromodomain antagonist (BA) JQ1 attenuates MYC and cyclin-dependent kinase (CDK)4/6, inhibits the nuclear RelA levels and the expression of NF-κB target genes, including Bruton tyrosine kinase (BTK) in MCL cells. Although lowering the levels of the antiapoptotic B-cell lymphoma (BCL)2 family proteins, BA treatment induces the proapoptotic protein BIM and exerts dose-dependent lethality against cultured and primary MCL cells. Cotreatment with BA and the BTK inhibitor ibrutinib synergistically induces apoptosis of MCL cells. Compared with each agent alone, cotreatment with BA and ibrutinib markedly improved the median survival of mice engrafted with the MCL cells. BA treatment also induced apoptosis of the in vitro isolated, ibrutinib-resistant MCL cells, which overexpress CDK6, BCL2, Bcl-xL, XIAP, and AKT, but lack ibrutinib resistance-conferring BTK mutation. Cotreatment with BA and panobinostat (pan-histone deacetylase inhibitor) or palbociclib (CDK4/6 inhibitor) or ABT-199 (BCL2 antagonist) synergistically induced apoptosis of the ibrutinib-resistant MCL cells. These findings highlight and support further in vivo evaluation of the efficacy of the BA-based combinations with these agents against MCL, including ibrutinib-resistant MCL.
authors.affiliation: Departments of Leukemia and Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Baohua
authors.initials: B
authors.lastname: Sun
authors.affiliation: Cancer Research, Houston Methodist Research Institute, Houston, TX;
authors.forename: Bhavin
authors.initials: B
authors.lastname: Shah
authors.affiliation: Departments of Leukemia and Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Warren
authors.initials: W
authors.lastname: Fiskus
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA;
authors.forename: Jun
authors.initials: J
authors.lastname: Qi
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX;
authors.forename: Kimal
authors.initials: K
authors.lastname: Rajapakshe
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX;
authors.forename: Cristian
authors.initials: C
authors.lastname: Coarfa
authors.affiliation: Laboratory of Translational Cancer Research, Tom and Gayle Benson Cancer Center, New Orleans, LA; and.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Cancer Research, Houston Methodist Research Institute, Houston, TX;
authors.forename: Santhana G T
authors.initials: SG
authors.lastname: Devaraj
authors.affiliation: Department of Internal Medicine, University of Utah Huntsman Cancer Institute, Salt Lake City, UT.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Departments of Leukemia and Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Departments of Leukemia and Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Michael L
authors.initials: ML
authors.lastname: Wang
authors.affiliation: Departments of Leukemia and Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Dyana T
authors.initials: DT
authors.lastname: Saenz
authors.affiliation: Departments of Leukemia and Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Stephanie
authors.initials: S
authors.lastname: Krieger
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA;
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Departments of Leukemia and Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Kapil N
authors.initials: KN
authors.lastname: Bhalla
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001381:Azepines / Q000494:pharmacology / Q000627:therapeutic use*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D051996:Transcription Factor RelA / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use*; D000092468:Bromodomain Containing Proteins
chemical_list: D000225:Adenine; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000970:Antineoplastic Agents; D001381:Azepines; D018797:Cell Cycle Proteins; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D016328:NF-kappa B; D009687:Nuclear Proteins; D010880:Piperidines; D011505:Protein-Tyrosine Kinases; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D011720:Pyrazoles; D011743:Pyrimidines; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C551803:ibrutinib; C000625949:BTK protein, human; C000625951:Btk protein, mouse