title: CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL.
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.
authors.affiliation: Celgene Corporation, Summit, NJ;
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Hagner
authors.affiliation: Celgene Corporation, Summit, NJ;
authors.forename: Hon-Wah
authors.initials: HW
authors.lastname: Man
authors.affiliation: Celgene Corporation, Sevilla, Spain;
authors.forename: Celia
authors.initials: C
authors.lastname: Fontanillo
authors.affiliation: Celgene Corporation, San Diego, CA; and.
authors.forename: Maria
authors.initials: M
authors.lastname: Wang
authors.affiliation: Celgene Corporation, San Diego, CA; and.
authors.forename: Suzana
authors.initials: S
authors.lastname: Couto
authors.affiliation: Celgene Corporation, San Diego, CA; and.
authors.forename: Mike
authors.initials: M
authors.lastname: Breider
authors.affiliation: Celgene Corporation, Summit, NJ;
authors.forename: Chad
authors.initials: C
authors.lastname: Bjorklund
authors.affiliation: Celgene Corporation, San Diego, CA; and.
authors.forename: Courtney G
authors.initials: CG
authors.lastname: Havens
authors.affiliation: Celgene Corporation, San Diego, CA; and.
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.affiliation: Celgene Corporation, San Diego, CA; and.
authors.forename: Emily
authors.initials: E
authors.lastname: Rychak
authors.affiliation: Celgene Corporation, San Diego, CA; and.
authors.forename: Heather
authors.initials: H
authors.lastname: Raymon
authors.affiliation: Celgene Corporation, San Diego, CA; and.
authors.forename: Rama Krishna
authors.initials: RK
authors.lastname: Narla
authors.affiliation: Celgene Corporation, San Diego, CA; and.
authors.forename: Leo
authors.initials: L
authors.lastname: Barnes
authors.affiliation: Celgene Corporation, San Diego, CA; and.
authors.forename: Gody
authors.initials: G
authors.lastname: Khambatta
authors.affiliation: Celgene Corporation, Summit, NJ;
authors.forename: Hsiling
authors.initials: H
authors.lastname: Chiu
authors.affiliation: Celgene Corporation, Summit, NJ;
authors.forename: Jolanta
authors.initials: J
authors.lastname: Kosek
authors.affiliation: Celgene Corporation, Summit, NJ;
authors.forename: Jian
authors.initials: J
authors.lastname: Kang
authors.affiliation: Celgene Corporation, Summit, NJ;
authors.forename: Michael D
authors.initials: MD
authors.lastname: Amantangelo
authors.affiliation: Celgene Corporation, Summit, NJ;
authors.forename: Michelle
authors.initials: M
authors.lastname: Waldman
authors.affiliation: Celgene Corporation, San Diego, CA; and.
authors.forename: Antonia
authors.initials: A
authors.lastname: Lopez-Girona
authors.affiliation: Celgene Corporation, Summit, NJ;
authors.forename: Ti
authors.initials: T
authors.lastname: Cai
authors.affiliation: Celgene Corporation, San Francisco, CA.
authors.forename: Michael
authors.initials: M
authors.lastname: Pourdehnad
authors.affiliation: Celgene Corporation, Sevilla, Spain;
authors.forename: Matthew
authors.initials: M
authors.lastname: Trotter
authors.affiliation: Celgene Corporation, San Diego, CA; and.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Daniel
authors.affiliation: Celgene Corporation, Summit, NJ;
authors.forename: Peter H
authors.initials: PH
authors.lastname: Schafer
authors.affiliation: Celgene Corporation, Summit, NJ;
authors.forename: Anke
authors.initials: A
authors.lastname: Klippel
authors.affiliation: Celgene Corporation, Summit, NJ;
authors.forename: Anjan
authors.initials: A
authors.lastname: Thakurta
authors.affiliation: Celgene Corporation, Summit, NJ;
authors.forename: Rajesh
authors.initials: R
authors.lastname: Chopra
authors.affiliation: Celgene Corporation, Summit, NJ;
authors.forename: Anita K
authors.initials: AK
authors.lastname: Gandhi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics* / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000378:metabolism; D007372:Interferons / Q000235:genetics / Q000378:metabolism; D000077269:Lenalidomide; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D018716:Molecular Mimicry; D010447:Peptide Hydrolases / Q000235:genetics* / Q000378:metabolism; D010881:Piperidones / Q000737:chemistry / Q000494:pharmacology*; D059748:Proteolysis / Q000187:drug effects; D052999:Quinazolinones / Q000737:chemistry / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases; D023041:Xenograft Model Antitumor Assays
chemical_list: C000602306:3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione; D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; C502543:CRBN protein, human; C497239:IKZF1 protein, human; C106285:IKZF3 protein, human; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; D010881:Piperidones; D052999:Quinazolinones; D034741:RNA, Small Interfering; D051740:Ikaros Transcription Factor; D013792:Thalidomide; D007372:Interferons; C467566:pomalidomide; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; D000077269:Lenalidomide