The thalidomide-like drug lenalidomide is used to treat multiple myeloma, but its mechanism of action is not known. Two studies have shown that lenalidomide induces proteasomal degradation of Ikaros family zinc finger protein 1 (IKZF1) and IKZF3 through cereblon (CRBN), a substrate-recognition component of a cullin-dependent ubiquitin ligase. Loss of IKZF1 and IKZF3 was required for the therapeutic effect of lenalidomide. Other studies have shown that inhibition of CRBN and stabilization of its substrates mediates the limb defects observed following in utero exposure to thalidomide-like drugs. Therefore, these results in multiple myeloma imply that these drugs do not simply inhibit CRBN, but modify the substrate specificity of CRBN, and that the teratogenic and anticancer effects of thalidomide-like drugs can be uncoupled.
References
Krönke, J. et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science http://dx.doi.org/10.1126/science.1244851 (2013)
Lu, G. et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science http://dx.doi.org/10.1126/science.1244917 (2013)
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Seton-Rogers, S. Destruction of Ikaros. Nat Rev Cancer 14, 9 (2014). https://doi.org/10.1038/nrc3663
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DOI: https://doi.org/10.1038/nrc3663
