Singapore researchers have identified adenosine deaminase acting on RNA1 (ADAR1) as a novel driver of acquired resistance to lenalidomide in multiple myeloma, according to findings published in the journal Blood on March 13, 2025. The study reveals a previously unknown mechanism that could potentially be targeted to overcome treatment resistance in patients who no longer respond to this critical therapy.
A team led by Dr. Mun Yee Koh and Dr. Teoh Phaik Ju from the Cancer Science Institute of Singapore at the National University of Singapore discovered that ADAR1 plays a crucial role in suppressing the immune response triggered by lenalidomide, which is essential for killing multiple myeloma cells.
Understanding Lenalidomide Resistance
Multiple myeloma is a cancer affecting plasma cells in the bone marrow. While immunomodulatory drugs (IMiDs) like lenalidomide have significantly improved survival rates, many patients eventually develop resistance, leading to disease relapse.
Lenalidomide works by binding to cereblon (CRBN), which promotes the proteasomal degradation of IKZF1 and IKZF3, preventing multiple myeloma cells from growing while stimulating immunomodulatory effects. However, only 20-30% of resistance mechanisms can be attributed to CRBN alterations, leaving most cases poorly understood until now.
"As new IMiD analogues, such as cereblon (CRBN) E3 ligase modulators, progress through clinical trials, and as there may be other drugs harboring similar pharmacological profile in the future, our findings on ADAR1 and the [double-stranded RNA]–sensing mechanism in [multiple myeloma] are highly pertinent," the researchers stated in their published report.
The Role of ADAR1 in Immune Suppression
The research team analyzed RNA sequencing data from multiple myeloma cells treated with lenalidomide or pomalidomide, as well as molecular profiling data from patients in the CoMMpass study. They found that lenalidomide activates the MDA5-mediated double-stranded RNA–sensing pathway in multiple myeloma cells, leading to ADAR1-regulated, interferon-mediated cell death.
When ADAR1 was overexpressed, the cells showed reduced sensitivity to lenalidomide, increased RNA editing, and suppression of RNA-sensing pathways. Conversely, ADAR1 loss sensitized myeloma cells to immunomodulatory drugs by activating these pathways and boosting interferon responses.
Professor Chng Wee Joo, one of the study collaborators, explained: "ADAR1 inhibits lenalidomide's activity by editing double-stranded RNA, thus hindering the immune response and reducing the effectiveness of the drug in combating multiple myeloma growth and proliferation."
Therapeutic Implications and Future Directions
The discovery adds a new dimension to understanding how multiple myeloma patients develop resistance to IMiDs, highlighting the role of double-stranded RNA pathways beyond the previously understood CRBN pathway.
The findings suggest that targeting ADAR1 could offer a promising strategy to overcome resistance to lenalidomide. With ADAR1 inhibitors currently in preclinical development, combining these with lenalidomide or newer CRBN E3 ligase modulators (CELMoDs) could potentially provide more effective treatment approaches.
"By reducing the levels of ADAR1 and increasing double-stranded RNA accumulation in multiple myeloma cells, we could increase the sensitivity of the cells to lenalidomide," noted Dr. Koh. "This would, in turn, lead to the activation of immune responses and kill the multiple myeloma cells."
The research team plans to further investigate ADAR1's role in alternative splicing in multiple myeloma, which could uncover additional opportunities for therapeutic intervention. These ongoing efforts aim to develop more effective strategies for overcoming IMiD resistance and improving outcomes for patients with multiple myeloma.
As clinical trials continue to explore the potential of new IMiD analogues and CRBN E3 ligase modulators, this research provides valuable insights that may guide the development of more effective drug combinations to overcome treatment resistance in multiple myeloma.
