2. Academic Validation
  3. CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL

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.
Patrick R Hagner 1,  Hon-Wah Man 1,  Celia Fontanillo 2,  Maria Wang 3,  Suzana Couto 3,  Mike Breider 3,  Chad Bjorklund 1,  Courtney G Havens 3,  Gang Lu 3,  Emily Rychak 3,  Heather Raymon 3,  Rama Krishna Narla 3,  Leo Barnes 3,  Gody Khambatta 3,  Hsiling Chiu 1,  Jolanta Kosek 1,  Jian Kang 1,  Michael D Amantangelo 1,  Michelle Waldman 1,  Antonia Lopez-Girona 3,  Ti Cai 1,  Michael Pourdehnad 4,  Matthew Trotter 2,  Thomas O Daniel 3,  Peter H Schafer 1,  Anke Klippel 1,  Anjan Thakurta 1,  Rajesh Chopra 1,  Anita K Gandhi 1
Affiliations

Affiliations

  • 1 Celgene Corporation, Summit, NJ;
  • 2 Celgene Corporation, Sevilla, Spain;
  • 3 Celgene Corporation, San Diego, CA; and.
  • 4 Celgene Corporation, San Francisco, CA.
PMID: 26002965 DOI: 10.1182/blood-2015-02-628669
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.

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