Immunomodulatory drugs disrupt the cereblon–CD147–MCT1 axis to exert antitumor activity and teratogenicity
Abstract
Immunomodulatory drugs (IMiDs), such as thalidomide and its derivatives lenalidomide and pomalidomide, are key treatment modalities for hematologic malignancies, particularly multiple myeloma (MM) and del(5q) myelodysplastic syndrome (MDS). Cereblon (CRBN), a substrate receptor of the CRL4 ubiquitin ligase complex, is the primary target by which IMiDs mediate anticancer and teratogenic effects. Here we identify a ubiquitin-independent physiological chaperone-like function of CRBN that promotes maturation of the basigin (BSG; also known as CD147) and solute carrier family 16 member 1 (SLC16A1; also known as MCT1) proteins. This process allows for the formation and activation of the CD147-MCT1 transmembrane complex, which promotes various biological functions, including angiogenesis, proliferation, invasion and lactate export. We found that IMiDs outcompete CRBN for binding to CD147 and MCT1, leading to destabilization of the CD147-MCT1 complex. Accordingly, IMiD-sensitive MM cells lose CD147 and MCT1 expression after being exposed to IMiDs, whereas IMiD-resistant cells retain their expression. Furthermore, del(5q) MDS cells have elevated CD147 expression, which is attenuated after IMiD treatment. Finally, we show that BSG (CD147) knockdown phenocopies the teratogenic effects of thalidomide exposure in zebrafish. These findings provide a common mechanistic framework to explain both the teratogenic and pleiotropic antitumor effects of IMiDs.
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Zebrafish and chicken were reported to exhibit defects to limb/fin formation upon exposure to thalidomide or knock-down of Crbn, partially resembling thalidomide-induced defects.
“these were reported to exhibit defects to limb/fin formation upon exposure to thalidomide or knock-down of Crbn (Eichner et al., 2016; Ito et al., 2010), partially resembling thalidomide-induced defects.”
From Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome (2018) · cites this paper as Eichner et al., 2016
The first class of additional molecular glue degraders comprises aryl sulfonamides, including indisulam, tasisulam, E7820 and chloroquinoxaline.
“The first class comprises aryl sulfonamides, including indisulam, tasisulam, E7820 and chloroquinoxaline”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [173]
Aryl sulfonamides have produced modest response rates as monotherapy in clinical trials involving patients with advanced-stage solid tumours.
“which to date have produced modest response rates as monotherapy in clinical trials involving patients with advanced-stage solid tumours173–176.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [173]
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“CRL4 has further been implicated in the IMiD-independent turnover of GLUL, BSG, and MEIS2 (Eichner et al., 2016; Krönke et al., 2014; Nguyen et al., 2016; Fischer et al., 2014), and regulation of AMPK (Lee et al.”
BackgroundInfluentialpSILAC mass spectrometry reveals ZFP91 as IMiD-dependent substrate of the CRL4CRBN ubiquitin ligase
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- Authors
- Eichner, R., Heider, M., Fernández-Sáiz, V., van Bebber, F., Garz, A.-K., Lemeer, S., Rudelius, M., Targosz, B.-S., Jacobs, L., Knorn, A.-M., Slawska, J., Platzbecker, U., Germing, U., Langer, C., Knop, S., Einsele, H., Peschel, C., Haass, C., Keller, U., Schmid, B., Götze, K. S., Kuster, B., & Bassermann, F.
- Affiliations
- TUM Klinikum (DE)
- German Cancer Research Center (DE)
- Technical University of Munich (DE)
- University of Würzburg (DE)
- University Hospital Carl Gustav Carus (DE)
- Heinrich Heine University Düsseldorf (DE)
- Universität Ulm (DE)
- Universitätsklinikum Würzburg (DE)
- German Center for Neurodegenerative Diseases (DE)
- Corresponding author
- Bassermann, Florian
- ORCID
- Venue
- Nature Medicine
- Published
- 2016-06-13
- Volume
- 22
- Issue
- 7
- Pages
- 735-743
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2434407168
- Cited by
- 183
- References
- 53
- Citations by year
- 2026: 6 · 2025: 17 · 2024: 17 · 2023: 15 · 2022: 26 · 2021: 18 · 2020: 22 · 2019: 16 · 2018: 22 · 2017: 18 · 2016: 6
- FWCI
- 19.67
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- DZNE Pub (submittedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- immunomodulators, thalidomide, lenalidomide, pomalidomide, cereblon, CD147, MCT1, lactate transporters, multiple myeloma, del(5q) myelodysplastic syndrome, teratogenicity, drug resistance
- MeSH terms
- Lenalidomide, Humans, Immunologic Factors, Immunosuppressive Agents, Multiple Myeloma, Myelodysplastic Syndromes, Peptide Hydrolases, RNA, Messenger, Thalidomide, Signal Transduction, Oncogene Proteins, Cell Cycle Proteins, Reverse Transcriptase Polymerase Chain Reaction, Ubiquitin-Protein Ligases, Adaptor Proteins, Signal Transducing, Basigin, Teratogenesis
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