title: Proteasomal Inhibition by Ixazomib Induces CHK1 and MYC-Dependent Cell Death in T-cell and Hodgkin Lymphoma.
abstract: Proteasome-regulated NF-κB has been shown to be important for cell survival in T-cell lymphoma and Hodgkin lymphoma models. Several new small-molecule proteasome inhibitors are under various stages of active preclinical and clinical development. We completed a comprehensive preclinical examination of the efficacy and associated biologic effects of a second-generation proteasome inhibitor, ixazomib, in T-cell lymphoma and Hodgkin lymphoma cells and in vivo SCID mouse models. We demonstrated that ixazomib induced potent cell death in all cell lines at clinically achievable concentrations. In addition, it significantly inhibited tumor growth and improved survival in T-cell lymphoma and Hodgkin lymphoma human lymphoma xenograft models. Through global transcriptome analyses, proteasomal inhibition showed conserved overlap in downregulation of cell cycle, chromatin modification, and DNA repair processes in ixazomib-sensitive lymphoma cells. The predicted activity for tumor suppressors and oncogenes, the impact on "hallmarks of cancer," and the analysis of key significant genes from global transcriptome analysis for ixazomib strongly favored tumor inhibition via downregulation of MYC and CHK1, its target genes. Furthermore, in ixazomib-treated lymphoma cells, we identified that CHK1 was involved in the regulation of MYC expression through chromatin modification involving histone H3 acetylation via chromatin immunoprecipitation. Finally, using pharmacologic and RNA silencing of CHK1 or the associated MYC-related mechanism, we demonstrated synergistic cell death in combination with antiproteasome therapy. Altogether, ixazomib significantly downregulates MYC and induces potent cell death in T-cell lymphoma and Hodgkin lymphoma, and we identified that combinatorial therapy with anti-CHK1 treatment represents a rational and novel therapeutic approach. Cancer Res; 76(11); 3319-31. ©2016 AACR.
authors.affiliation: Division of Hematology Oncology and Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
authors.forename: Dashnamoorthy
authors.initials: D
authors.lastname: Ravi
authors.affiliation: Division of Hematology Oncology and Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
authors.forename: Afshin
authors.initials: A
authors.lastname: Beheshti
authors.affiliation: Division of Hematology Oncology and Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
authors.forename: Nasséra
authors.initials: N
authors.lastname: Abermil
authors.affiliation: Division of Hematology Oncology and Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
authors.forename: Frank
authors.initials: F
authors.lastname: Passero
authors.affiliation: Division of Hematology Oncology and Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
authors.forename: Jaya
authors.initials: J
authors.lastname: Sharma
authors.affiliation: Division of Hematology Oncology and Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
authors.forename: Michael
authors.initials: M
authors.lastname: Coyle
authors.affiliation: Division of Hematology Oncology and Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
authors.forename: Athena
authors.initials: A
authors.lastname: Kritharis
authors.affiliation: Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois.
authors.forename: Irawati
authors.initials: I
authors.lastname: Kandela
authors.affiliation: Center of Cancer Systems Biology, Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: Lynn
authors.initials: L
authors.lastname: Hlatky
authors.affiliation: New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, Massachusetts.
authors.forename: Michail V
authors.initials: MV
authors.lastname: Sitkovsky
authors.affiliation: Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois.
authors.forename: Andrew
authors.initials: A
authors.lastname: Mazar
authors.affiliation: University of Maryland, Baltimore, Maryland.
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Gartenhaus
authors.affiliation: Division of Hematology Oncology and Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts. AEvens@tuftsmedicalcenter.org.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Evens
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001896:Boron Compounds / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D000071877:Checkpoint Kinase 1 / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006689:Hodgkin Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D016399:Lymphoma, T-Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D001896:Boron Compounds; C489427:MYC protein, human; D061988:Proteasome Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C548400:ixazomib; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D046988:Proteasome Endopeptidase Complex; D005998:Glycine