CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL
Patrick R Hagner1, Hon-Wah Man1, Celia Fontanillo2
1Celgene Corporation, Summit, NJ;
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.
Insights
The novel pleiotropic pathway modifier CC-122 targets Cereblon (CRBN), degrading Aiolos and Ikaros transcription factors. This mechanism drives anti-lymphoma activity in diffuse large B-cell lymphoma (DLBCL) cells.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Cereblon (CRBN) is a key target for immunomodulatory drugs like lenalidomide and pomalidomide.
- These drugs induce ubiquitination and degradation of transcription factors Aiolos and Ikaros by binding to CRBN.
- Understanding CRBN's role is crucial for developing targeted cancer therapies.
Purpose of the Study:
- To investigate the mechanism of action of the new chemical entity CC-122, a pleiotropic pathway modifier.
- To determine if CC-122 binds to CRBN and affects its known substrates, Aiolos and Ikaros.
- To elucidate the anti-lymphoma activity of CC-122 in diffuse large B-cell lymphoma (DLBCL).
Main Methods:
- In vitro and in vivo studies using DLBCL cell lines and patient samples.
- Assays to detect CC-122 binding to CRBN.
- Analysis of Aiolos and Ikaros protein levels and ubiquitination.
- Short hairpin RNA (shRNA) mediated knockdown of Aiolos and Ikaros.
- Measurement of interferon-stimulated gene transcription and apoptosis induction.
Main Results:
- CC-122 binds to CRBN and promotes the degradation of Aiolos and Ikaros in DLBCL and T cells.
- CC-122-induced degradation of Aiolos and Ikaros leads to increased transcription of interferon-stimulated genes.
- This effect is independent of interferon production and results in apoptosis in both ABC and GCB DLBCL cell lines.
Conclusions:
- CC-122 exhibits cell-of-origin independent anti-lymphoma activity in DLBCL.
- The mechanism involves CRBN-mediated degradation of Aiolos and Ikaros, leading to immunostimulatory effects.
- CC-122's activity contrasts with lenalidomide, which is selective for the ABC subtype of DLBCL.
More Related Videos
08:19Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
Published on: July 20, 2019
08:52Generation of Multivirus-specific T Cells to Prevent/treat Viral Infections after Allogeneic Hematopoietic Stem Cell Transplant
Published on: May 27, 2011
Related Concept Videos
01:27Cytotoxic T Cells-mediated Immune Response
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...
01:31The Intrinsic Apoptotic Pathway
01:30Inhibitors of Viral Protein Synthesis
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:57Targeted Cancer Therapies