Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells
2014
Krönke, Jan | Udeshi, Namrata D. | Narla, Anupama | Grauman, Peter | Hurst, Slater N. | McConkey, Marie | Svinkina, Tanya | Heckl, Dirk | Comer, Eamon | Li, Xiaoyu | Ciarlo, Christie | Hartman, Emily | Munshi, Nikhil | Schenone, Monica | Schreiber, Stuart L. | Carr, Steven A. | Ebert, Benjamin L.
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.
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