Novel insights into the mechanism of action of lenalidomide

Editorial Lenalidomide (Revlimid ®) is a synthetic derivative of thalidomide (Thalomid ®) currently licensed by the US Food and Drug Administration (FDA) and other international regulatory agencies for the treatment of multiple myeloma (MM) (in combination with dexamethasone) 1-3 and low or intermediate-1 risk myelodysplastic syndromes bearing 5q cytogenetic abnormalities (as a standalone agent). 4-6 Lenalidomide was originally developed to improve the safety profile of thalidomide, which eventually turned out to be responsible for an estimated number of 10 000–20 000 phocomelic babies worldwide in the 1950–60s. 7 As compared with thalidomide, lenalidomide is associated with limited neurotoxic activity, but is not completely devoid of teratogenic effects. For this reason, both thalidomide (which is also approved for use in MM patients, together with dexamethasone) 11 and lenalidomide are commercialized under tightly controlled distribution programs (as per explicit request of the US FDA). 8 Recently, a novel thalidomide derivative, pomalidomide (Pomalyst ®), has been approved for the treatment of specific subsets of MM patients, including individuals who progressed on or shortly after thalidomide therapy. At odds with thalidomide and lenalidomide, pomalidomide exerts very limited (if any) teratogenic activity. 14 Throughout the 2000s, thalidomide and lenalidomide have been the subjects of an intense wave of investigation, revealing multiple biological effects that could account for their antineoplastic activity. In particular, lenalidomide has been shown to (1) limit the proliferation of cancer cells and promote their death; (2) interrupt the trophic support provided to malignant cells by the tumor stroma; and (3) operate as a pleiotropic immunomodulator. Owing to their ability to boost both the innate and adaptive arm of the immune response, thalidomide, lenalidomide, and pomalidomide are collectively referred to as immunomodulatory drugs (IMiDs). In spite of the acute interest generated by IMiDs throughout the past decade, the actual molecular target of these drugs has been discovered only in 2010, when thalidomide was shown to physically interact with (and hence inhibit) the E3 ubiquitin ligase cereblon (CRBN). 22 Zebrafish (Danio rerio) embryos exposed to thalidomide developed limb abnormalities that mimicked human phocomelia, unless they expressed a variant of CRBN that does not bind IMiDs (CRBN YWAA). 22 Importantly, developmental limb defects also manifested in CRBN-deficient zebrafish, indicating that the teratogenic effects of thalidomide stem from CRBN inhibition. 22,23 Apparently in contrast with this notion, lenalidomide and pomalidomide were subsequently suggested to stabilize CRBN, 24 thus decreasing the half-life of several proteins that are …