Editors' ChoiceCancer

Drug with a (Re)Purpose

Sci. Signal.  21 Jan 2014:
Vol. 7, Issue 309, pp. ec18
DOI: 10.1126/scisignal.2005081

Thalidomide, once infamous for its deleterious effects on fetal development, has reemerged 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. and Krönke et al. 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 “repurposing” a ubiquitin ligase.

J. Krönke, N. D. Udeshi, A. Narla, P. Grauman, S. N. Hurst, M. McConkey, T. Svinkina, D. Heckl, E. Comer, X. Li, C. Ciarlo, E. Hartman, N. Munshi, M. Schenone, S. L. Schreiber, S. A. Carr, B. L. Ebert, Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343, 301–305 (2014). [Abstract] [Full Text]

G. Lu, R. E. Middleton, H. Sun, M. Naniong, C. J. Ott, Constantine S. Mitsiades, K.-K. Wong, J. E. Bradner, W. G. Kaelin Jr., The myeloma drug lenalidomide promotes the cereblon-dependent destruction of ikaros proteins. Science 343, 305–309 (2014). [Abstract] [Full Text]

A. K. Stewart, How thalidomide works against cancer. Science 343, 256–257 (2014). [Abstract] [Full Text]