Proposed mannequin of mechanism underlying the function of ADAR1 in regulating resistance to IMiDs in MM. Credit score: Blood (2024). DOI: 10.1182/blood.2024024429
A brand new examine performed by researchers from the Most cancers Science Institute of Singapore (CSI Singapore) on the Nationwide College of Singapore has uncovered a key mechanism behind lenalidomide resistance in a number of myeloma (MM), providing new insights into potential methods for enhancing remedy outcomes and overcoming drug resistance.
The staff, led by Dr. Teoh Phaik Ju and Dr. Koh Mun Yee, along with Professor Chng Wee Joo and Affiliate Professor Polly Chen, recognized a gene known as ADAR1, which encodes an RNA-editing enzyme as a key think about suppressing the immune response triggered by lenalidomide—an immune-stimulating drug, important to killing MM cells. The findings have been revealed within the journal Blood on 13 March 2025.
ADAR1’s function in lenalidomide resistance in MM
MM is a sort of most cancers that impacts plasma cells within the bone marrow. Whereas standard-of-care therapies like lenalidomide, an immunomodulatory drug (IMiD), have improved survival charges for a lot of MM sufferers, a big quantity nonetheless expertise relapse as a result of growth of drug resistance.
Lenalidomide works by binding to a protein known as cereblon (CRBN), which breaks down a number of proteins which can be important for MM cell survival and progress. Nevertheless, many sufferers finally cease responding to the drug, resulting in illness relapse.
Whereas 20% to 30% of the resistance circumstances have been linked to defects in CRBN and its related elements, the underlying mechanisms in most resistance circumstances have remained poorly understood. This examine experiences new findings demonstrating that ADAR1 abnormalities result in a suppressed immune system in IMiD-resistant MM circumstances.
Overcoming drug resistance
ADAR1 inhibits lenalidomide’s exercise by modifying double-stranded RNA (dsRNA), thus hindering the immune response and lowering the effectiveness of the drug in combating MM progress and proliferation. The researchers found that by lowering the degrees of ADAR1 and growing dsRNA accumulation in MM cells, they may enhance the sensitivity of the cells to lenalidomide. This might, in flip, result in the activation of the immune responses and kill the MM cells.
The invention provides a brand new layer to the understanding of how MM sufferers could turn into immune to IMiD, highlighting the function of dsRNA pathways past the beforehand understood CRBN pathway.
The findings additionally counsel that focusing on ADAR1 and the dsRNA pathway may provide promising methods to beat resistance to lenalidomide in MM. As medical trials proceed to discover the potential of recent IMiD analogs, akin to CRBN-E3 ligase modulators (CELMoDs) and different medication with comparable pharmacological profile, combining these therapies with ADAR1 inhibitors could present a simpler strategy to sort out drug resistance and enhance affected person outcomes.
With ADAR1 inhibitors at the moment in preclinical growth, this technique holds nice promise for advancing remedy choices for MM. As well as, the analysis staff plans to additional examine ADAR1’s function in different splicing, a post-transcriptional gene regulatory mechanism, in MM, which may uncover much more alternatives for therapies.
Extra data:
Mun Yee Koh et al, The ADAR1-regulated cytoplasmic dsRNA-sensing pathway is a novel mechanism of lenalidomide resistance in a number of myeloma, Blood (2024). DOI: 10.1182/blood.2024024429
Journal data:
Blood
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Nationwide College of Singapore
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