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BIOMARKER:

CRBN expression

i
Other names: CRBN, Cereblon, Protein Cereblon, Mental Retardation, Non-Syndromic, Autosomal Recessive, 2A, Protein X 0001, MRT2A, MRT2
Entrez ID:
Related biomarkers:
3ms
NCI-2016-00073: Gossypol Acetic Acid With Lenalidomide and Dexamethasone in Treating Patients With Relapsed Symptomatic Multiple Myeloma (clinicaltrials.gov)
P1, N=10, Completed, Mayo Clinic | Active, not recruiting --> Completed | Phase classification: P1/2 --> P1 | Trial completion date: Dec 2024 --> Dec 2023
Trial completion • Phase classification • Trial completion date • Combination therapy • IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • CRBN (Cereblon) • MAPK1 (Mitogen-activated protein kinase 1)
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BCL2 expression • CRBN expression
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lenalidomide • R-(-)-gossypol (AT 101)
5ms
RRMM and Post-BCMA Treated Subjects from the CC-220-MM-001 Study Show Increased Genomic Aberrations Associated with High-Risk and Significant Dysfunction in CD4+ T-Cell Compartment Compared to NDMM Subjects (ASH 2023)
Conclusions These data illustrate that late-line RRMM subjects have appreciable immunosuppression compared to NDMM subjects, with particular dysfunction in the CD4+ helper T-cell compartment, suggesting that the efficacy of immunotherapies in late line myeloma may benefit from combinations with agents that improve CD4+ T-cell function. These data also show enrichment of molecular high-risk segments and CRBN-related genomic aberrations in RRMM subjects in the CC-220-MM-001 study.
Clinical • PD(L)-1 Biomarker • IO biomarker
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KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • CD8 (cluster of differentiation 8) • PD-1 (Programmed cell death 1) • CRBN (Cereblon) • CD4 (CD4 Molecule) • ICOS (Inducible T Cell Costimulator) • SDC1 (Syndecan 1)
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KRAS mutation • NRAS mutation • PD-1 expression • CRBN expression • CRBN mutation
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iberdomide (CC-220)
5ms
EZH2 Inhibition Overcomes Immunomodulatory Drug (IMiD) Resistance in Multiple Myeloma Cell Lines in a Cereblon Pathway Dependent Manner (ASH 2023)
Following concentration/duration optimisation, cell lines were treated with EZH2i (Tazemetostat) 0.25-1µM or DMSO control for 5 days alone, and then in combination with IMiD (Lenalidomide, Len, 0-20 µM, Pomalidomide, Pom, 0-8 µM) or CELMoD (Iberdomide, CC-220, 0-2 µM and Mezigdomide, CC-92480, 0-0.1uM) for a further 5 days. Conclusions Our results suggest that combining EZH2i with IMiDs/CELMoDs can overcome resistance to these agents in MM cell line models, with synergy that is CRBN-dependent. By examining the key components of the CRBN pathway we identified that EZH2i reduced H3K27me3 and increased Ikaros and Aiolos association at the IRF4 promoter, suggesting a possible re-coupling of Ikaros/Aiolos to IRF4 expression, which may be responsible for reinstating IMiD/CELMoD activity, driving the synergistic effect seen.
Preclinical • Immunomodulating
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EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • IKZF1 (IKAROS Family Zinc Finger 1) • CRBN (Cereblon) • IRF4 (Interferon regulatory factor 4) • ANXA5 (Annexin A5)
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CRBN expression • IKZF2 expression • IRF4 expression
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lenalidomide • Tazverik (tazemetostat) • pomalidomide • iberdomide (CC-220) • mezigdomide (CC-92480)
6ms
High levels of CRBN isoform lacking IMiDs binding domain predicts for a worse response to IMiDs-based upfront therapy in newly diagnosed myeloma patients. (PubMed, Clin Exp Med)
In sight of this, in the present study, we evaluated the CRBN expression, both full-length and spliced isoforms, by using real-time assay data from 87 patients and RNA sequencing data from 50 patients (n = 137 newly diagnosed MM patients), aiming at defining CRBN's role as a predictive biomarker for response to IMiDs-based induction therapy. We found that the expression level of the spliced isoform tends to be higher in not-responding patients, confirming that the presence of a more CRBN spliced transcript predicts for lack of IMiDs response.
Journal
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CRBN (Cereblon)
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CRBN expression
7ms
ZnDDC, a novel CELMoD-like agent binding to DDB1-CRBN complex demonstrates significant synergism with BTZ and IMiDs and overcomes IMiDs resistance in myeloma cell lines and primary samples (IMW 2023)
Introduction: Although immunomodulatory imide drugs (IMiDs), also called CRBN E3 ligase modulatory drugs (CELMoDs), e.g., lenalidamide (LEN), pomalidomide (POM) and proteasome inhibitor [bortezomib (BTZ)] improved the survival rate of multiple myeloma (MM), all MM patients are relapsed due to drug resistance...Disulfiram (DS), an anti-alcoholism drug used in clinic for over 60 years, demonstrates excellent specific anticancer activity with no/low toxicity to normal tissues... ZnDDC demonstrates CELMoD like property with synergistic effect when used in combination with clinically available IMiDs and BTZ; The effect of ZnDDC is potentially CRL4CRBN-IKZF1/3-IRF4 pathway dependent; Further study is ongoing which could translate this work into MM clinic in a fast track.
Preclinical
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MYC (V-myc avian myelocytomatosis viral oncogene homolog) • IKZF1 (IKAROS Family Zinc Finger 1) • CRBN (Cereblon) • IKZF3 (IKAROS Family Zinc Finger 3) • IL2 (Interleukin 2) • DDB1 (Damage Specific DNA Binding Protein 1)
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CRBN expression
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bortezomib • pomalidomide
8ms
RXR Agonists Enhance Lenalidomide Anti-Myeloma Activity and T Cell Functions while Retaining Glucose-Lowering Effect. (PubMed, Cells)
We investigated the effects of RXR agonists (LG100754, bexarotene, AGN194204, and LG101506) on lenalidomide's anti-myeloma activity, T cell functions, and the level of glucose and lipids in vivo. LG100754 retained its glucose- and lipid-lowering effects. RXR agonists demonstrate potential utility in enhancing drug sensitivity and T-cell function in the treatment of myeloma.
Journal
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CRBN (Cereblon)
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CRBN expression
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lenalidomide • IRX4204 • Targretin oral (bexarotene oral)
8ms
New P1 trial • IO biomarker
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IKZF1 (IKAROS Family Zinc Finger 1) • CRBN (Cereblon)
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CRBN expression
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Empliciti (elotuzumab) • Hemady (dexamethasone tablets) • mezigdomide (CC-92480) • dexamethasone injection
10ms
Dual inhibition of CDK4/6 and XPO1 induced senescence with acquired vulnerability to CRBN-based PROTAC drugs (EACR 2023)
Through a senolytic-drug screen, CRBN-based PROTAC ARV-825 was identified as an agent that can selectively kill senescent liver cancer cells...Mechanistically, USP2 directly interacts with CRBN, leading to the deubiquitination and stabilization of CRBN in senescent liver cancer cells.ConclusionOur study demonstrates the striking synergy of inducing senescence in liver cancer cells through the combination of CDK4/6 inhibitor and XPO1 inhibitor. These findings also shed light on the molecular processes underlying the vulnerability of senescent liver cancer cells to CRBN-based PROTAC therapy and suggest a potential therapeutic strategy for liver cancer treatment.
IO biomarker
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HER-2 (Human epidermal growth factor receptor 2) • CDK4 (Cyclin-dependent kinase 4) • CRBN (Cereblon)
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CRBN expression
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ARV-825
11ms
MOLECULAR MECHANISMS OF RESISTANCE TO IMMUNOMODULATORS IN MULTIPLE MYELOMA: AN IN VITRO STUDY (EHA 2023)
Different IMiDs are currently used in clinical practice in combination with PI, such as Lenalidomide (LEN) and Pomalidomide (POM), having both cereblon as the main target...Aims: This project's focus was to evaluate the molecular mechanism of resistance to IMiDs resistance, namely LEN and POM, in MM cells and assess the cross-resistance to Bortezomib (BTZ)... The resistant models developed show different degrees of resistance according to IMiD and cell line. In LEN- resistant models, H929-RL and U-266RL cells presented an IC 25 6.5x and over 1000x higher compared to parental cells, respectively. The U-266RP cells showed an IC 25 500x higher than U-266 cells.
Preclinical • IO biomarker • Immunomodulating
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MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • ABCB1 (ATP Binding Cassette Subfamily B Member 1) • CRBN (Cereblon) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2) • ABCG2 (ATP Binding Cassette Subfamily G Member 2) • NQO1 (NAD(P)H dehydrogenase, quinone 1) • REL (REL Proto-Oncogene) • RELA (RELA Proto-Oncogene) • SLC2A1 (Solute Carrier Family 2 Member 1)
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BCL2 expression • MYC expression • CRBN expression • NFE2L2 expression
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lenalidomide • bortezomib • pomalidomide • thalidomide
12ms
HIGH EXPRESSION OF NUCLEAR CEREBLON IS ASSOCIATED WITH LONGER SURVIVAL IN PATIENTS WITH MULTIPLE MYELOMA TREATED WITH IMIDS (EMN 2023)
Per HOVON-87/NMSG-18 trial protocol, these patients were treated with thalidomide or lenalidomide combined with melphalan and prednisone followed by thalidomide/lenalidomide maintenance (i.e. MPT-T or MPR-R). In conclusion, higher expression of nuclear CRBN was associated with a superior PFS and OS upon MPT or MPR treatment. Levels of nuclear CRBN protein, possibly in combination with IRF-4, may represent a biomarker for predicting treatment outcome in patients treated with IMiDs.
Clinical
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MYC (V-myc avian myelocytomatosis viral oncogene homolog) • IKZF1 (IKAROS Family Zinc Finger 1) • CRBN (Cereblon) • IRF4 (Interferon regulatory factor 4)
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CRBN expression
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lenalidomide • prednisone • thalidomide • melphalan
1year
Cereblon inhibits prostate cancer progression and metastasis by negatively regulating 6PGD (AACR 2023)
Our findings show convincingly that carbohydrate metabolism regulated by 6PGD is linked to prostate cancer metastasis via CRBN. Based on these data, we propose that the 6PGD-CRBN axis may be a suitable target for further research into new therapeutics for mitigating prostate cancer metastasis.
Late-breaking abstract
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CRBN (Cereblon) • PGD (Phosphogluconate Dehydrogenase)
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CRBN expression
over1year
The PROTAC selectively degrading Bcl-x represents a novel Hedgehog pathway inhibitor with capacity of combating resistance to Smoothened inhibitors while sparing bone growth. (PubMed, Theranostics)
Moreover, treatment with SIAIS361034 results in no impairment on the bone growth of young mice, accompanying no alteration of the expression of Bcl-x and Gli1 proteins. Our findings demonstrate that selectively targeting Bcl-x by PROTAC is a promising strategy for combating resistance to Smo inhibitors without causing on-target drug toxicities of bone growth.
Journal • IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • CRBN (Cereblon) • SMO (Smoothened Frizzled Class Receptor) • GLI1 (GLI Family Zinc Finger 1) • GLI2 (GLI Family Zinc Finger 2)
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SMO mutation • CRBN expression
over1year
Mechanistic Studies and a Retrospective Cohort Study: The Interaction between PPAR Agonists and Immunomodulatory Agents in Multiple Myeloma. (PubMed, Cancers (Basel))
Lenalidomide and fenofibrate showed opposite effects on acylcarnitines and amino acids. Co-administration of immunomodulatory drugs and PPAR agonists was associated with inferior treatment responses and poor survival. Our study provides the first evidence that PPAR agonists reduce CRBN expression through various mechanisms including inducing methylation of CRBN promoter CpG island, enhancing CRBN protein degradation, and affecting metabolomics of MM cells.
Retrospective data • Journal
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CRBN (Cereblon)
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CRBN expression
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lenalidomide
over1year
CRBN Structural Changes, Copy Number Changes and COP9 Signalosome Subunits Gene Expression Mediate Sensitivity to New Celmod Compound CC-92480 in Multiple Myeloma Patients (ASH 2022)
All 5 patients were exposed in previous lines to lenalidomide and pomalidomide. All patients were treated with CC-92480 in combination with dexamethasone...Streptavidin pulldown and immunoprecipitation assays showed decreased binding of thalidomide, DDB1 and CUL4A to R309H-CRBN mutant compared to WT-CRBN... We here defined in primary patient plasma cells the mechanisms of resistance to the novel CELMoD CC-92480 to be driven by biallelic CRBN copy number loss or alteration of its structure, resulting from CRBN mutations or splicing (exon 10) coupled with monoallelic 3p loss. COP9 signalosome subunits gene expression decreased in resistant patients and may also play a critical role in CELMoD sensitivity.
Clinical
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TP53 (Tumor protein P53) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • IKZF1 (IKAROS Family Zinc Finger 1) • CRBN (Cereblon) • CUL4A (Cullin 4A) • IKZF3 (IKAROS Family Zinc Finger 3) • DDB1 (Damage Specific DNA Binding Protein 1) • COPS3 (COP9 Signalosome Subunit 3) • GPS1 (G Protein Pathway Suppressor 1)
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MYC expression • CRBN expression • CRBN mutation
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lenalidomide • dexamethasone • pomalidomide • thalidomide • mezigdomide (CC-92480)
over1year
Elucidating the Role of ADAR1 in Regulating Immunotherapeutic Response in Multiple Myeloma (ASH 2022)
The development of immunomodulatory drugs (IMiDs) such as lenalidomide has profound immunostimulatory effects and direct anti-MM activity; however, acquired resistance to IMiDs commonly underlies relapse, rendering MM largely incurable...The potential role of ADAR1 in modulating immunotherapeutic responses may help unravel potential resistance mechanisms and identify novel therapeutic strategies. Current studies involve elucidating the association of ADAR1 with CRBN pathway.
IO biomarker
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IKZF1 (IKAROS Family Zinc Finger 1) • CRBN (Cereblon) • IKZF3 (IKAROS Family Zinc Finger 3) • ADAR (Adenosine Deaminase RNA Specific) • IFIH1 (Interferon Induced With Helicase C Domain 1)
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CRBN expression • ADAR overexpression
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lenalidomide
over1year
Evaluation of the Prognostic Significance of Cereblon Protein Expression in Multiple Myeloma. (PubMed, Clin Lab)
In this study, the survival time of the patients who received treatment regimens containing protease inhibitors and IMiD was longer, independent of the presence of strong nuclear CRBN expression. The survival rate was significantly higher in those who used IMiD and protease inhibitors in combination. Since the survival rate was found to be increased in IgG positive cases and we thought that evaluation of immunoglobulin tissue expression in MM cases can provide prognostic prediction.
Journal
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CRBN (Cereblon)
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CRBN expression
over1year
PPAR agonists attenuate lenalidomide's anti-myeloma activity in vitro and in vivo. (PubMed, Cancer Lett)
High PPAR expression was correlated with poor clinical outcomes. Our study provides the first evidence that PPARs transcriptionally regulate CRBN and that drug-drug interactions between PPAR agonists and IMiDs may impact myeloma treatment outcomes.
Preclinical • Retrospective data • Journal
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CRBN (Cereblon) • PPARA (Peroxisome Proliferator Activated Receptor Alpha)
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CRBN expression
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lenalidomide
almost2years
Drug resistance and minimal residual disease in multiple myeloma. (PubMed, Cancer Drug Resist)
Multicolor flow cytometry, or next-generation flow, and next-generation sequencing are currently the techniques available to measure MRD with sensitivity at 10. Sustained MRD negativity is related to prolonged survival, and it is evaluated in all recent clinical trials as a surrogate of drug efficacy.
Review • Journal • IO biomarker • Minimal residual disease
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IKZF1 (IKAROS Family Zinc Finger 1) • CRBN (Cereblon) • IKZF3 (IKAROS Family Zinc Finger 3) • IRF4 (Interferon regulatory factor 4)
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CRBN expression • IRF4 expression
almost2years
Oligo-Protac Strategy for Cell-Selective and Targeted Degradation of Activated Stat3 (ASGCT 2022)
Phthalimide derivatives, such as thalidomide, were tethered to the 3’ end of the decoy molecule without or with aliphatic linkers of different length...To our knowledge, this is the first demonstration that the PROTAC strategy can be employed to decoy DNA-based targeting of undruggable TFs. Our initial results underscore the potential of using this strategy for cell-selective targeting of oncogenic and immunosuppressive STAT3 with potential application to cancer immunotherapy.
IO biomarker
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CRBN (Cereblon) • STAT3 (Signal Transducer And Activator Of Transcription 3) • TLR9 (Toll Like Receptor 9) • STAT1 (Signal Transducer And Activator Of Transcription 1) • STAT5A (Signal Transducer And Activator Of Transcription 5A)
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CRBN expression
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thalidomide
almost2years
Redefining CD56 as a biomarker and therapeutic target in Multiple Myeloma. (PubMed, Mol Cancer Res)
CD56 signaling promotes MM growth and adhesion, by activating CREB1 target genes, MCL1 and BCL2. Inhibition of CREB1 alone or in combination with lenalidomide is an unexplored synthetic lethal approach in CD56-expressing MM patients.
Journal • IO biomarker
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CRBN (Cereblon) • NCAM1 (Neural cell adhesion molecule 1) • CREB1 (CAMP Responsive Element Binding Protein 1) • RPS6KA3 (Ribosomal Protein S6 Kinase A3)
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NCAM1 expression • CRBN expression
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lenalidomide
2years
Multiple Myeloma Patient Tumors With High Levels of Cereblon Exon-10 Deletion Splice Variant Upregulate Clinically Targetable Pro-Inflammatory Cytokine Pathways. (PubMed, Front Genet)
Immunomodulatory drugs (IMiDs), including lenalidomide and pomalidomide, are used in the routine treatment for multiple myeloma (MM) patients...Interestingly, we found that an EZH2 sensitivity gene expression signature also correlated with high BATF or venetoclax sensitivity scores in these tumors. Together, these data provide a rationale for investigating EZH2 inhibitors or venetoclax in combination with the next generation CRBN-targeting agents, such as CELMoDs, for patients overexpressing the CRBN exon-10 splice variant.
Journal
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IFNG (Interferon, gamma) • IKZF1 (IKAROS Family Zinc Finger 1) • CRBN (Cereblon) • TNFA (Tumor Necrosis Factor-Alpha) • IL10 (Interleukin 10)
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CRBN expression • CRBN overexpression
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Venclexta (venetoclax) • lenalidomide • Tazverik (tazemetostat) • pomalidomide
2years
Gene Mutation and Overexpression of Newly Diagnosed Multiple Myeloma Patients (PubMed, Zhongguo Shi Yan Xue Ye Xue Za Zhi)
There are multiple gene mutations and overexpression in NDMM. However, there is no dominated single mutation or overexpression of genes. The most common gene mutations are those in the RAS/MAPK pathway and the genes of cyclin family CCND are overexpression.
Journal • IO biomarker
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KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • FGFR3 (Fibroblast growth factor receptor 3) • CCND1 (Cyclin D1) • CRBN (Cereblon) • CCND2 (Cyclin D2) • CCND3 (Cyclin D3) • PRDM1 (PR/SET Domain 1) • TENT5C (Terminal Nucleotidyltransferase 5C)
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MYC overexpression • FGFR3 overexpression • CCND1 overexpression • CRBN expression • CRBN overexpression • KRAS overexpression • Chr del(13)(q14) • FGF3 overexpression
over2years
Overcoming IMiD Resistance in T-cell Lymphomas Through Potent Degradation of ZFP91 and IKZF1. (PubMed, Blood)
Using mass spectrometry, we show that CC-92480 selectively degrades IKZF1 and ZFP91 in TCL cells with greater potency than pomalidomide. Moreover, lenalidomide-sensitive TCLs can acquire stable resistance via ZFP91 rewiring, which involves casein kinase 2 (CK2) mediated c-Jun inactivation. Overall, these findings identify a critical transcription factor network within TCLs and provide clinical proof of concept for the novel therapy using next-generation degraders.
Journal
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IKZF1 (IKAROS Family Zinc Finger 1) • CRBN (Cereblon) • JUN (Jun proto-oncogene)
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CRBN expression
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lenalidomide • pomalidomide • mezigdomide (CC-92480)
over2years
EP300 selectively controls the enhancer landscape of MYCN-amplified neuroblastoma. (PubMed, Cancer Discov)
JQAD1 treatment causes loss of H3K27ac at CRC enhancers and rapid neuroblastoma apoptosis, with limited toxicity to untransformed cells where CBP may compensate. Further, JQAD1 activity is critically determined by cereblon (CRBN) expression across neuroblastoma cells.
Journal
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MYCN (MYCN Proto-Oncogene BHLH Transcription Factor) • CRBN (Cereblon) • EP300 (E1A binding protein p300)
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MYCN amplification • CRBN expression
over2years
ARV-825 Demonstrates Antitumor Activity in Gastric Cancer via MYC-Targets and G2M-Checkpoint Signaling Pathways. (PubMed, Front Oncol)
ARV-825 displayed higher anticancer efficiency in gastric cancer cells than OTX015 and JQ1. ARV-825, a BRD4 inhibitor, could effectively suppress the growth and elevate the apoptosis of gastric cancer cells via transcription downregulation of c-MYC and PLK1. These results implied that ARV-825 could be a good therapeutic strategy to treat gastric cancer.
Journal • PARP Biomarker
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MYC (V-myc avian myelocytomatosis viral oncogene homolog) • CRBN (Cereblon) • PLK1 (Polo Like Kinase 1) • CASP3 (Caspase 3) • BRD4 (Bromodomain Containing 4)
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MYC expression • CRBN expression • CRBN overexpression
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JQ-1 • birabresib (OTX015) • ARV-825
over2years
CD56 Has a Critical Role in Regulating Multiple Myeloma Cell Growth and Response to Therapies (ASH 2021)
In conclusion, our study defines an effective threshold for therapeutic intervention in CD56-expressing MM patients. Moreover, our data pioneer the use of CREB1/RSK2 inhibition in CD56-expressing MM cells, either as single agents or in combination with lenalidomide, suggesting that CD56 can be a prognostic and predictive factor of response in MM.
IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • CRBN (Cereblon) • NCAM1 (Neural cell adhesion molecule 1) • SDC1 (Syndecan 1) • CREB1 (CAMP Responsive Element Binding Protein 1) • RPS6KA3 (Ribosomal Protein S6 Kinase A3)
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Chr t(11;14) • NCAM1 expression • SDC1 positive • CRBN expression • CD5 overexpression
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lenalidomide
over2years
Immunomodulatory effect of NEDD8-activating enzyme inhibition in Multiple Myeloma: upregulation of NKG2D ligands and sensitization to Natural Killer cell recognition. (PubMed, Cell Death Dis)
Moreover, inhibition of neddylation can cooperate with immunomodulatory drugs (IMiDs) in upregulating MICA surface levels in MM cells due to increased expression of CRBN, the cellular target of these drugs. In summary, MLN4924/Pevonedistat sensitizes MM to NK cell recognition, adding novel information on the anticancer activity of neddylation inhibition.
Journal
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CRBN (Cereblon) • IKZF3 (IKAROS Family Zinc Finger 3) • NKG2D (killer cell lectin like receptor K1)
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CRBN expression
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pevonedistat (MLN4924)
over2years
Prediction Model for Cereblon Expression in Bone Marrow Plasma Cells Based on Blood Markers in Multiple Myeloma Patients. (PubMed, Front Oncol)
Based on these results, we constructed a new nomogram model to predict high CRBN expression and the effectiveness of IMiD therapy in multiple myeloma. This nomogram could improve the prognostic evaluation of myeloma patients exhibiting high CRBN expression treated with IMiD therapy and might help provide personalized treatment strategies to clinicians.
Clinical • Journal
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CRBN (Cereblon) • B2M (Beta-2-microglobulin)
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CRBN expression