Dr. Leleu receives research support, lecture fees, and honoraria from Celgene.
Some readers will recall vividly the tragic events of the late 1950s and early 1960s when more than 10,000 children worldwide were born with deformities due to the teratogenic effects of thalidomide that had been prescribed for pregnancy-associated nausea and vomiting. Recently, Ito and colleagues identified cereblon (CRBN) as a primary target of thalidomide teratogenicity.1 Those investigators showed that binding of thalidomide to CRBN interrupts the function of the E3 ubiquitin ligase complex, resulting in down-regulation of expression of fibroblast growth factor genes. A number of mechanisms (e.g., antiangiogenic, proapoptotic, antiproliferative, immunomodulatory) have been suggested as the basis of the tumoricidal activity of thalidomide, but the findings of Ito et al. led Zhu and colleagues in the laboratory of Keith Stewart at Mayo Clinic, Arizona, to investigate the role of CRBN in the anti-myeloma effects of thalidomide and two other related immunomodulatory drugs (IMiDs), lenalidomide and pomalidomide.
Those investigators demonstrated that both absence and downregulation of expression of CRBN in human myeloma cells resulted in IMiD resistance in human myeloma cells. Cells with stable CRBN depletion were resistant to IMiDs but not to unrelated myeloma drugs bortezomib, dexamethasone, and melphalan. Moreover, using a myeloma cell line, deletion of the gene that encodes CRBN was found to mark cells that had been selected in culture for resistance to IMiDs, and gene-expression profiling showed a 40-fold reduction in CRBN expression in the resistant cells. In patients characterized as resistant to lenalidomide, CRBN levels in paired samples (before and after initiation of IMiD therapy) were lower at the time that drug-resistance was noted. Gene knock-down experiments showed that inhibition of CRBN expression caused a reduction in expression of interferon regulatory factor 4 (IRF4), one of the known targets of lenalidomide.
In Brief
The studies of Zhu and colleagues suggest that CRBN plays a central role in the anti-myeloma activity of IMiDs, perhaps because CRBN and IMiDs work in concert to down-regulate expression of IRF4. However, mechanisms of resistance that do not involve quantitative expression of CRBN are likely to exist. This hypothesis is supported by the observation that while most patients become resistant to IMiDs, few unselected cases show genomic abnormalities affecting CRBN. In these cases, resistance may be a consequence of aberrant expression of molecules downstream of CRBN or of modulation of completely different pathways targeted by IMiDs. Still, CRBN expression appears to be an essential requirement for activity of these compounds as loss of expression renders myeloma cells resistant to this class of drugs. The current study supports the aphorism that to better understand the mechanisms of action of a drug, one must unravel its mechanisms of resistance. The current findings suggest that quantifying expression of CRBN may be a useful biomarker for assessing sensitivity/resistance to IMiDs in patients with myeloma. Understanding the CRBN-dependent basis of the anti-myeloma effects of IMiDs may lead to development of novel agents with antitumor activity distinct from the teratogenic effects associated with currently available IMiDs.
