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Haematological cancer

Ikaros—not a myth for myeloma

Nature Reviews Clinical Oncology volume 11, page 65 (2014)Cite this article

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Lenalidomide is a powerful drug for the treatment of multiple myeloma and other B-cell lymphomas. Two independent groups, respectively, led by Benjamin Ebert and William Kaelin, recently reported that degradation of the ikaros proteins, IKZF1 and IKZF3, is the main event underlying lenalidomide antineoplastic function, finally shedding some light on the mechanisms of action of this drug.

The remarkable clinical activity of lenalidomide and its analogues thalidomide and pomalidomide (collectively immunomodulatory drugs or IMiDs) is eclipsed by their teratogenic effect, which limits their use. Recent studies have demonstrated that IMiDs bind to and inactivate the cereblon E3 ubiquitin ligase and that loss of cereblon could explain the teratogenicity of the drugs. “In myeloma cells, high levels of cereblon are associated with responsiveness, while a low level of cereblon renders cells resistant to IMiD treatment, indicating that the therapeutic activity of thalidomide-like drugs is actually due to a new activity of cereblon when bound to these agents,” explains Kaelin.

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References

  1. Kronke, J. et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 10.1126/science.1244851

  2. Lu, G. et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of ikaros proteins. Science 10.1126/science.1244917

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Authors
  1. Alessia Errico
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Errico, A. Ikaros—not a myth for myeloma. Nat Rev Clin Oncol 11, 65 (2014). https://doi.org/10.1038/nrclinonc.2013.237

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