Researchers have found a key gene responsible for resistance to lenalidomide treatment for multiple myeloma, it has been announced.
The Singapore-based researchers have been studying a gene called ADAR1, which, they say, is a key factor in suppressing the immune response triggered by the immunomodulatory drug lenalidomide.
Lenalidomide binds to the cereblon protein, and mutations in cereblon and its associated proteins has been linked to lenalidomide resistance, but only in around 20-30% of cases. Little is known about what drives resistance in the remaining cases.
Reporting in Blood, they say that ADAR1 edits double stranded RNA (dsRNA) to hinder the immune response. They have undertaken studies that show that reducing levels of ADAR1 – and the subsequent accumulation of dsRNA – increases the sensitivity of cells to the drug treatment.
Researchers Dr Teoh Phaik Ju and Dr Koh Mun Yee, of the National University of Singapore, say: “The discovery adds a new layer to the understanding of how multiple myeloma patients may become resistant to immunomodulatory drugs, highlighting the role of dsRNA pathways beyond the previously understood cereblon pathway.”
They state: “With ADAR1 inhibitors currently in preclinical development, this strategy holds great promise for advancing treatment options for multiple myeloma.
“In addition, the research team plans to further investigate ADAR1’s role in alternative splicing, a post-transcriptional gene regulatory mechanism, in multiple myeloma, which could uncover even more opportunities for treatments.”
Source:
Koh MY, Chung TH, Tang NXN, Toh SHM, Zhou J, Tan TK, Chen L, Chng WJ, Teoh PJ. (2025) “The ADAR1-regulated cytoplasmic dsRNA-sensing pathway is a novel mechanism of lenalidomide resistance in multiple myeloma.” Blood, 13 March 2025, doi: 10.1182/blood.2024024429.
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