The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins

By G. Lu, R. Middleton, Huahang Sun, MarkVic Naniong, Christopher J. Ott, C. Mitsiades, Kwok-kin Wong, James E. Bradner, W. Kaelin. Science, 2013

1,381 citations recorded by the source corpus.

Drug With a (Re)Purpose Thalidomide, once infamous for its deleterious effects on fetal development, has re-emerged as a drug of great interest because of its beneficial immunomodulatory effects. A derivative drug called lenalidomide significantly extends the survival of patients with multiple myeloma, but the molecular mechanisms underlying its efficacy remain unclear (see the Perspective by Stewart). Building on a previous observation that thalidomide binds to cereblon, a ubiquitin ligase, Lu et al. (p. 305, published online 28 November) and Krönke et al. (p. 301, published online 28 November) show that in the presence of lenalidomide, cereblon selectively targets two B cell transcription factors (Ikaros family members, IKZF1 and IKZF3) for degradation. In myeloma cell lines and patient cells, down-regulation of IKZF1 and IKZF3 was necessary and sufficient for the drug's anticancer activity. Thus, lenalidomide may act, at least in part, by “grepurposing” a ubiquitin ligase. A drug with potent activity in multiple myeloma patients acts by inducing degradation of two specific transcription factors. [Also see Perspective by Stewart] Thalidomide-like drugs such as lenalidomide are clinically important treatments for multiple myeloma and show promise for other B cell malignancies. The biochemical mechanisms underlying their antitumor activity are unknown. Thalidomide was recently shown to bind to, and inhibit, the cereblon ubiquitin ligase. Cereblon loss in zebrafish causes fin defects reminiscent of the limb defects seen in children exposed to thalidomide in utero. Here we show that lenalidomide-bound cereblon acquires the ability to target for proteasomal degradation two specific B cell transcription factors, Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3). Analysis of myeloma cell lines revealed that loss of IKZF1 and IKZF3 is both necessary and sufficient for lenalidomide’s therapeutic effect, suggesting that the antitumor and teratogenic activities of thalidomide-like drugs are dissociable.

Subfields: Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/78bec298ec2a26703ac77b2d1a6e38c4778689df

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Citations in the corpus

Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN (2018, methodology): “C], but only C-x(2)-”
Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15 (2017, methodology): “For example, the clinical activity of IMiDs in multiple myeloma is the result of ubiquitination and degradation of two transcription factors, IKZF1 (Ikaros) and IKZF3 (Aiolos) (5, 6).”
Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. (2015, background): “OTX015 is currently in phase I clinical trials and pomalidomide is a potent third-generation immunomodulatory drug (IMiD), which functions through interacting with the E3 ligase cereblon and inducing degradation of essential Ikaros transcription factors in MM (Boi et al., 2015; Lu et al., 2014).”
Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS (2015, background): “b, Immunoblot of CK1α protein levels in the bone marrow (1,2) and peripheral blood (3,4) mononuclear cells of AML patients treated with lenalidomide as part of a clinical trial.”
Lessons in PROTAC design from selective degradation with a promiscuous warhead (2017, background): “The immunomodulatory imide drug thalidomide and its analogs have been shown to bind to CRBN and induce degradation of several neosubstrate proteins (Chamberlain et al., 2014; Krönke et al., 2014; Lu et al., 2014).”
Thalidomide‐induced teratogenesis: History and mechanisms (2015, background): “…with Cereblon and can selectively activate downstream targets Ikaros and Aiolos to be recruited for degradation and help mediate their action in multiple myeloma, further indicating that the anti-tumor and teratogenic actions of the drug can be dissociated (Kronke et al., 2014; Lu et al., 2014).”
Plasticity in binding confers selectivity in ligand induced protein degradation (2018, positive): “…the potent anti-cancer drugs thalidomide, lenalidomide and pomalidomide (collectively known as IMiDs for immuno-modulatory drugs) exert their therapeutic effects through induced degradation of key efficacy targets, such as IKZF1, IKZF3 12–14 , ZFP91 15 , or casein kinase 1 alpha (Ck1 α ) 16,17 .”