Work

Mutations in CRBN and other cereblon pathway genes are infrequently associated with acquired resistance to immunomodulatory drugs

Year: 2021

Type: article

Abstract: Immunomodulatory drugs (IMiDs) are the current backbone of standard and experimental combination myeloma therapies at all stages of the disease. However, the majority of patients inevitably relapse and the mechanisms of resistance are still poorly understood. Previous studies looking for genetic drivers of resistance have looked for changes in core members of the CRL4 CRBN E3-ubiquitin ligase complex (CUL4-RBX1-DDB1-CRBN) and identified mutations in the protein to which IMiDs bind, cereblon (CRBN), but at a rate that cannot account for resistance in the majority of patients [ 1 , 2 ]. Several in vitro studies have now identified novel upstream and downstream regulators of CRBN activity that could have a role in IMiD resistance and have not been previously examined in patient samples [ 3 , 4 , 5 , 6 ]. In this study paired presentation and relapse samples from newly diagnosed patients recruited to a clinical trial of IMiD therapies were used to investigate the role of mutations in all genes currently implicated in IMiD activity. Infrequent mutations in CRBN itself were identified that could be a cause of IMiD resistance in some patients. CRBN and other genes in the IMiD response pathway were mutated at low frequency and, in many cases, at low clonal fraction suggesting that mechanisms other than mutations, for example post-translational modification or epigenetic alterations, may underlie resistance acquisition.

Source: Leukemia

DOI: 10.1038/s41375-021-01373-4