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Immunomodulatory drugs (IMiDs), such as lenalidomide, thalidomide, pomalidomide, and CC-220, play a crucial role in the treatment of newly diagnosed patients with multiple myeloma (MM). Early diagnosis is critical as most patients will eventually develop resistance to therapy and experience a relapsing disease state.1 The primary target of IMiDs has been identified as the cereblon (CRBN) protein, with the binding of IMiDs altering substrate specificity and affecting the recruitment and degradation of proteins which in turn are involved in the regulation of survival, immune response, and tumor proliferation.2
Dr. Yuan Xiao Zhu, from the Division of Hematology, Mayo Clinic, AZ, USA, and colleagues generated lenalidomide resistant human multiple myeloma cell lines (HMCLs) by culturing the lenalidomide-sensitive isogenic cell lines MM.1S, KMS11, XG1, and OPM2, in the presence of increasing doses of lenalidomide (5 µM to 50 µM) for an extended period of time until resistant cells were generated.3
The authors concluded that a deficiency or mutation in CRBN is the most common mechanism of acquired resistance to IMiD therapy in MM cells. Furthermore, the researchers identified a novel mechanism of resistance involving the activation of STAT3 and IL6. In addition to this, the study illustrated a potential strategy to overcome IMiD resistance with inhibition of IRF and CBP/EP300.
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