Proteasomal inhibition by ixazomib induces CHK1 and MYC-dependent cell death in T-cell and Hodgkin lymphoma

Dashnamoorthy Ravi, Afshin Beheshti, Nassôera Abermil, Frank Passero, Jaya Sharma, Michael Coyle, Athena Kritharis, Irawati Kandela, Lynn Hlatky, Michail V. Sitkovsky, Andrew Mazar, Ronald B. Gartenhaus, Andrew M. Evens*

*Corresponding author for this work

Research output: Contribution to journalArticle

22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3319-3331
Number of pages13
JournalCancer Research
Volume76
Issue number11
DOIs
StatePublished - Jun 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Ravi, D., Beheshti, A., Abermil, N., Passero, F., Sharma, J., Coyle, M., Kritharis, A., Kandela, I., Hlatky, L., Sitkovsky, M. V., Mazar, A., Gartenhaus, R. B., & Evens, A. M. (2016). Proteasomal inhibition by ixazomib induces CHK1 and MYC-dependent cell death in T-cell and Hodgkin lymphoma. Cancer Research, 76(11), 3319-3331. https://doi.org/10.1158/0008-5472.CAN-15-2477