Mutations in CRBN and other cereblon pathway genes are infrequently associated with acquired resistance to immunomodulatory drugs

Jones, J.; Barber, Amy; Bihan, Yann‐Vaï Le; Weinhold, Niels; Ashby, Cody; Walker, Brian A.; Wardell, Christopher P.; Wang, H.; Kaiser, Martin; Jackson, GH; Davies, Faith E.; Chopra, Rajesh; Morgan, Gareth J.; Pawlyn, Charlotte

doi:10.1038/s41375-021-01373-4

Cited by 13 publications

(7 citation statements)

References 15 publications

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“…Recent molecular studies with lenalidomide- and pomalidomide-resistant MM patients revealed some CRBN molecular alterations (e.g., point mutation, structural variation, copy loss, or exon 10 spliced transcript of CRBN) associated with IMiDs’ exposure [ 26 ]. Nevertheless, the low frequency and clonal fraction of identified CRBN mutations cannot be responsible for IMIDs resistance in the majority of patients [ 27 , 28 ]. As IMiDs resistance is one of the main challenges in MM treatment, its mechanism of resistance needs to be explored in future studies.…”

Section: Immunomodulatory Drugs (Imids)mentioning

confidence: 99%

CRL4CRBN E3 Ligase Complex as a Therapeutic Target in Multiple Myeloma

Barankiewicz

Salomon-Perzyński

Misiewicz-Krzemińska

et al. 2022

Cancers

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Multiple myeloma (MM) is the second most common hematological malignancy with a recurrent clinical course. The introduction of immunomodulatory drugs (IMiDs) was one of the milestones in MM therapy leading to a significant improvement in patients’ prognosis. Currently, IMiDs are the backbone of MM therapy in newly diagnosed and relapsed/refractory settings. It is now known that IMiDs exert their anti-myeloma activity mainly by binding cereblon (CRBN), the substrate receptor protein of the CRL4 E3 ubiquitin ligase (CRL4CRBN) complex. By binding CRBN, IMiDs alter its substrate specificity, leading to ubiquitination and proteasomal degradation of proteins essential for MM cell survival. Following the success of IMiDs, it is not surprising that the possibility of using the CRL4CRBN complex’s activity to treat MM is being further explored. In this review, we summarize the current state of knowledge about novel players in the MM therapeutic landscape, namely the CRBN E3 ligase modulators (CELMoDs), the next generation of IMiDs with broader biological activity. In addition, we discuss a new strategy of tailored proteolysis called proteolysis targeting chimeras (PROTACs) using the CRL4CRBN to degrade typically undruggable proteins, which may have relevance for the treatment of MM and other malignancies in the future.

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Section: Immunomodulatory Drugs (Imids)mentioning

confidence: 99%

CRL4CRBN E3 Ligase Complex as a Therapeutic Target in Multiple Myeloma

Barankiewicz

Salomon-Perzyński

Misiewicz-Krzemińska

et al. 2022

Cancers

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“…Suggesting an association to IMiD resistance, another CRBN mutation has been identified in a patient unresponsive to initial lenalidomide and later pomalidomide treatment, this mutation is located in close proximity to the IMiD-binding site of the gene ( 58 ). A specific CRBN mutation (p.Cys326Gly) has also been detected at relapse in a patient treated with lenalidomide showing that this mutation contributed to lenalidomide resistance and clinical relapse ( 80 ). The cysteine amino acid caused by this mutation is involved in the Zinc finger motif, leading to protein misfolding and aggregation which destabilizes the IMiD binding domain of the protein ( 81 ).…”

Section: Immunomodulatory Agentsmentioning

confidence: 99%

“…The presence of these CRBN aberrations were associated with significantly reduced PFS and OS in lenalidomide-refractory MM ( 82 ). Other mutations were detected in genes coding for the core CRL4CRBN E3-ligase complex and COP9 signalosome ( 80 ). There are 42 genes termed “CRBN/IMiD genes”, and 12/42 genes showed mutations in a dataset of 56 patients from the UK National Cancer Research Institute Myeloma XI trial at presentation, relapse or at both time points ( 80 ).…”

Section: Immunomodulatory Agentsmentioning

confidence: 99%

“…Other mutations were detected in genes coding for the core CRL4CRBN E3-ligase complex and COP9 signalosome ( 80 ). There are 42 genes termed “CRBN/IMiD genes”, and 12/42 genes showed mutations in a dataset of 56 patients from the UK National Cancer Research Institute Myeloma XI trial at presentation, relapse or at both time points ( 80 ). These mutations are associated with relapse after lenalidomide treatment since 9/17 mutations arose in patients who had received lenalidomide and 6/9 had a higher cancer clonal fraction (CCF) in the relapse sample, suggesting that they may have been selected for by exposure to treatment.…”

Section: Immunomodulatory Agentsmentioning

confidence: 99%

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Advances in the molecular characterization of multiple myeloma and mechanism of therapeutic resistance

Saldarriaga¹,

Darwiche²,

Jayabalan³

et al. 2022

Front. Oncol.

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Recent insight in the genomic landscape of newly diagnosed multiple myeloma (NDMM) and its precursor conditions, monoclonal gammopathy of uncertain significance (MGUS), and smoldering myeloma have allowed the identification of patients with precursor conditions with a high risk of progression. These cases with “progressor” MGUS/SMM have a higher average mutation burden, have higher rates of mutations in specific genes such as MAPK, DNA repair, MYC, DIS3, and are enriched for specific mutational signatures when compared to non-progressors and are comparable to those found in NDMM. The highly preserved clonal heterogeneity seen upon progression of SMM, combined with the importance of these early variables, suggests that the identification of progressors based on these findings could complement and enhance the currently available clinical models based on tumor burden. Mechanisms leading to relapse/refractory multiple myeloma (RRMM) are of clinical interest given worse overall survival in this population. An Increased mutational burden is seen in patients with RRMM when compared to NDMM, however, there is evidence of branching evolution with many of these mutations being present at the subclonal level. Likewise, alterations in proteins associated with proteosome inhibitor and immunomodulatory drugs activity could partially explain clinical resistance to these agents. Evidence of chromosomal events leading to copy number changes is seen, with the presence of TP53 deletion, mutation, or a combination of both being present in many cases. Additional chromosomal events such as 1q gain and amplification may also interact and lead to resistance.

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“…reported the association of genetic alterations of the CRBN gene, such as point mutations, structural abnormalities, and alternative splicing, with acquired resistance to both lenalidomide and pomalidomide in MM patients. However, the genetic changes in CRBN do not explain lenalidomide resistance in all cases, because the abnormalities, excluding exon 10 splicing, are detected in less than 10% of lenalidomide‐refractory cases 10,11 . Therefore, it is still important to explore additional mechanisms of lenalidomide resistance in MM.…”

Section: Introductionmentioning

confidence: 99%

c‐FOS is an integral component of the IKZF1 transactivator complex and mediates lenalidomide resistance in multiple myeloma

Osada

Kikuchi

Iha

et al. 2023

Clinical & Translational Med

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BackgroundThe immunomodulatory drug lenalidomide, which is now widely used for the treatment of multiple myeloma (MM), exerts pharmacological action through the ubiquitin‐dependent degradation of IKZF1 and subsequent down‐regulation of interferon regulatory factor 4 (IRF4), a critical factor for the survival of MM cells. IKZF1 acts principally as a tumour suppressor via transcriptional repression of oncogenes in normal lymphoid lineages. In contrast, IKZF1 activates IRF4 and other oncogenes in MM cells, suggesting the involvement of unknown co‐factors in switching the IKZF1 complex from a transcriptional repressor to an activator. The transactivating components of the IKZF1 complex might promote lenalidomide resistance by residing on regulatory regions of the IRF4 gene to maintain its transcription after IKZF1 degradation.MethodsTo identify unknown components of the IKZF1 complex, we analyzed the genome‐wide binding of IKZF1 in MM cells using chromatin immunoprecipitation‐sequencing (ChIP‐seq) and screened for the co‐occupancy of IKZF1 with other DNA‐binding factors on the myeloma genome using the ChIP‐Atlas platform.ResultsWe found that c‐FOS, a member of the activator protein‐1 (AP‐1) family, is an integral component of the IKZF1 complex and is primarily responsible for the activator function of the complex in MM cells. The genome‐wide screening revealed the co‐occupancy of c‐FOS with IKZF1 on the regulatory regions of IKZF1‐target genes, including IRF4 and SLAMF7, in MM cells but not normal bone marrow progenitors, pre‐B cells or mature T‐lymphocytes. c‐FOS and IKZF1 bound to the same consensus sequence as the IKZF1 complex through direct protein‐protein interactions. The complex also includes c‐JUN and IKZF3 but not IRF4. Treatment of MM cells with short‐hairpin RNA against FOS or a selective AP‐1 inhibitor significantly enhanced the anti‐MM activity of lenalidomide in vitro and in two murine MM models. Furthermore, an AP‐1 inhibitor mitigated the lenalidomide resistance of MM cells.ConclusionsC‐FOS determines lenalidomide sensitivity and mediates drug resistance in MM cells as a co‐factor of IKZF1 and thus, could be a novel therapeutic target for further improvement of the prognosis of MM patients.

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Mutations in CRBN and other cereblon pathway genes are infrequently associated with acquired resistance to immunomodulatory drugs

Cited by 13 publications

References 15 publications

CRL4CRBN E3 Ligase Complex as a Therapeutic Target in Multiple Myeloma

CRL4CRBN E3 Ligase Complex as a Therapeutic Target in Multiple Myeloma

Advances in the molecular characterization of multiple myeloma and mechanism of therapeutic resistance

c‐FOS is an integral component of the IKZF1 transactivator complex and mediates lenalidomide resistance in multiple myeloma

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