Reference Detail

Ref Type Journal Article
PMID (26988986)
Authors Ravi D, Beheshti A, Abermil N, Passero F, Sharma J, Coyle M, Kritharis A, Kandela I, Hlatky L, Sitkovsky MV, Mazar A, Gartenhaus RB, Evens AM
Title Proteasomal Inhibition by Ixazomib Induces CHK1 and MYC-Dependent Cell Death in T-cell and Hodgkin Lymphoma.
Journal Cancer research
Vol 76
Issue 11
Date 2016 Jun 01
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown Hodgkin's lymphoma not applicable Ixazomib Preclinical Actionable In a preclinical study, Ixazomib (MLN9708) inhibited survival and induced apoptosis in Hodgkin's lymphoma cell lines in culture, and reduced tumor volume in xenograft models (PMID: 26988986). 26988986
Unknown unknown lymphoma not applicable Ixazomib + JQ1 Preclinical Actionable In a preclinical study, Ixazomib (MLN9708) and JQ1 combination treatment resulted in increased apoptosis in T-cell lymphoma cells in culture (PMID: 26988986). 26988986
Unknown unknown lymphoma not applicable Ixazomib Preclinical Actionable In a preclinical study, Ixazomib (MLN9708) inhibited survival and induced apoptosis in T-cell lymphoma cell lines in culture, and reduced tumor volume in xenograft models (PMID: 26988986). 26988986
Unknown unknown Hodgkin's lymphoma not applicable AZD7762 + Ixazomib Preclinical Actionable In a preclinical study, Ixazomib (MLN9708) and AZD7762 combination treatment resulted in increased apoptosis in Hodgkin's lymphoma cells in culture (PMID: 26988986). 26988986
Unknown unknown Hodgkin's lymphoma not applicable Ixazomib + JQ1 Preclinical Actionable In a preclinical study, Ixazomib (MLN9708) and JQ1 combination treatment resulted in increased apoptosis in Hodgkin's lymphoma cells in culture (PMID: 26988986). 26988986