title: Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide.
abstract: The precise molecular mechanism of action and targets through which thalidomide and related immunomodulatory drugs (IMiDs) exert their antitumor effects remains unclear. We investigated the role of cereblon (CRBN), a primary teratogenic target of thalidomide, in the antimyeloma activity of IMiDs. CRBN depletion is initially cytotoxic to human myeloma cells, but surviving cells with stable CRBN depletion become highly resistant to both lenalidomide and pomalidomide, but not to the unrelated drugs bortezomib, dexamethasone, and melphalan. Acquired deletion of CRBN was found to be the primary genetic event differentiating isogenic MM1.S cell lines cultured to be sensitive or resistant to lenalidomide and pomalidomide. Gene expression changes induced by lenalidomide were dramatically suppressed in the presence of CRBN depletion, further demonstrating that CRBN is required for lenalidomide activity. Downstream targets of CRBN include interferon regulatory factor 4 (IRF4) previously reported to also be a target of lenalidomide. Patients exposed to, and putatively resistant to, lenalidomide had lower CRBN levels in paired samples before and after therapy. In summary, CRBN is an essential requirement for IMiD activity and a possible biomarker for the clinical assessment of antimyeloma efficacy.
authors.affiliation: Division of Hematology-Oncology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Yuan Xiao
authors.initials: YX
authors.lastname: Zhu
authors.forename: Esteban
authors.initials: E
authors.lastname: Braggio
authors.forename: Chang-Xin
authors.initials: CX
authors.lastname: Shi
authors.forename: Laura A
authors.initials: LA
authors.lastname: Bruins
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Schmidt
authors.forename: Scott
authors.initials: S
authors.lastname: Van Wier
authors.forename: Xiu-Bao
authors.initials: XB
authors.lastname: Chang
authors.forename: Chad C
authors.initials: CC
authors.lastname: Bjorklund
authors.forename: Rafael
authors.initials: R
authors.lastname: Fonseca
authors.forename: P Leif
authors.initials: PL
authors.lastname: Bergsagel
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Orlowski
authors.forename: A Keith
authors.initials: AK
authors.lastname: Stewart
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000077269:Lenalidomide; D008954:Models, Biological; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics*; D010447:Peptide Hydrolases / Q000235:genetics* / Q000378:metabolism; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D044767:Ubiquitin-Protein Ligases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D001897:Boronic Acids; C502543:CRBN protein, human; D007155:Immunologic Factors; D011719:Pyrazines; D034741:RNA, Small Interfering; D013792:Thalidomide; D000069286:Bortezomib; C467566:pomalidomide; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; D000077269:Lenalidomide