Ubiquitin ligases target specific proteins for degradation, and pharmacologic modulation of ubiquitin ligase activity has the potential for therapeutic efficacy in cancer by altering the abundance of proteins that are required for tumor cell survival. Thalidomide and its derivatives, lenalidomide and pomalidomide, represent the first class of drugs that act by binding and changing the activity of a specific ubiquitin ligase. These compounds bind the CRL4-CRBN ubiquitin ligase, inducing the ubiquitination and consequent degradation of specific protreins. Lenalidomide is a highly effective drug for the treatment of myelodysplastic syndrome (MDS) with del(5q), multiple myeloma, and some additional B cell lymphomas. In multiple myeloma cells, lenalidomide increases the binding of two substrates, IKZF1 and IKZF3, to the CRBN substrate adapter; increases the ubiquitination of these substrates; and causes the targeted degradation of IKZF1 and IKZF3, transcription factors that are essential for the differentiation and survival of plasma cells including multiple myeloma cells. In del(5q) MDS, lenalidomide targets CSNK1A1 for destruction. Haploinsufficiency for CSNK1A1, a gene located within the common deleted region on chromosome 5q, results in selective targeting of the del(5q) clone. Recent studies indicate that lenalidomide, pomalidomide, and thalidomide modulate the CRl4-CRBN ubiquitin ligase in distinct ways, raising the possibility that new molecules may induce degradation of other proteins, creating new therapeutic opportunities.

Citation Format: Benjamin Ebert. Novel targeted therapies in myelodysplastic syndrome. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY13-03. doi:10.1158/1538-7445.AM2015-SY13-03

©2015 American Association for Cancer Research.
2015