CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL

Blood. 2015 Aug 6;126(6):779-89. doi: 10.1182/blood-2015-02-628669. Epub 2015 May 22.

Abstract

Cereblon (CRBN), a substrate receptor of the Cullin 4 RING E3 ubiquitin ligase complex, is the target of the immunomodulatory drugs lenalidomide and pomalidomide. Recently, it was demonstrated that binding of these drugs to CRBN promotes the ubiquitination and subsequent degradation of 2 common substrates, transcription factors Aiolos and Ikaros. Here we report that CC-122, a new chemical entity termed pleiotropic pathway modifier, binds CRBN and promotes degradation of Aiolos and Ikaros in diffuse large B-cell lymphoma (DLBCL) and T cells in vitro, in vivo, and in patients, resulting in both cell autonomous as well as immunostimulatory effects. In DLBCL cell lines, CC-122-induced degradation or short hairpin RNA-mediated knockdown of Aiolos and Ikaros correlates with increased transcription of interferon (IFN)-stimulated genes independent of IFN-α, -β, and -γ production and/or secretion and results in apoptosis in both activated B-cell (ABC) and germinal center B-cell DLBCL cell lines. Our results provide mechanistic insight into the cell-of-origin independent antilymphoma activity of CC-122, in contrast to the ABC subtype selective activity of lenalidomide.

Publication types

  • Clinical Trial

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Ikaros Transcription Factor / genetics*
  • Ikaros Transcription Factor / metabolism
  • Interferon Regulatory Factor-7 / genetics
  • Interferon Regulatory Factor-7 / metabolism
  • Interferons / genetics
  • Interferons / metabolism
  • Lenalidomide
  • Lentivirus / genetics
  • Lentivirus / metabolism
  • Lymphoma, Large B-Cell, Diffuse / drug therapy*
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / metabolism
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Mice
  • Mice, SCID
  • Molecular Mimicry
  • Peptide Hydrolases / genetics*
  • Peptide Hydrolases / metabolism
  • Piperidones / chemistry
  • Piperidones / pharmacology*
  • Proteolysis / drug effects
  • Quinazolinones / chemistry
  • Quinazolinones / pharmacology*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology
  • Thalidomide / analogs & derivatives
  • Thalidomide / pharmacology
  • Ubiquitin-Protein Ligases
  • Xenograft Model Antitumor Assays

Substances

  • 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • CRBN protein, human
  • IKZF1 protein, human
  • IKZF3 protein, human
  • IRF7 protein, human
  • Interferon Regulatory Factor-7
  • Piperidones
  • Quinazolinones
  • RNA, Small Interfering
  • Ikaros Transcription Factor
  • Thalidomide
  • Interferons
  • pomalidomide
  • Ubiquitin-Protein Ligases
  • Peptide Hydrolases
  • Lenalidomide