Investigators have identified a key component inhibiting responses to lenalidomide in patients with multiple myeloma, according to the results of a study recently published in Blood. They identified adenosine deaminase acting on RNA1 (ADAR1) as a novel driver of acquired resistance to lenalidomide in multiple myeloma cells but believe its effects could potentially be overcome.
“As new IMiD [immunomodulatory drugs] 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 and may guide the development of more effective therapeutic strategies and drug combinations to overcome treatment resistance and improve patient outcomes,” the study authors, led by Mun Yee Koh, PhD, of the Cancer Science Institute of Singapore, National University of Singapore, said in their published report.
Study Methods and Results
The investigators sought to identify alternative mechanisms of resistance to immunomodulatory drugs such as lenalidomide, as between 20% and 30% of resistance mechanisms may be attributed to CRBN alterations and other alterations in its pathway. These drugs bind directly to CRBN and promote the proteasomal degradation of IKZF1 and IKZF3, which prevents multiple myeloma cells from growing and stimulates other immunomodulatory effects.
Dr. Koh and colleagues analyzed the RNA sequencing data of multiple myeloma cells that had been treated with lenalidomide or pomalidomide as well as molecular profiling data from patients in the CoMMpass study. Lenalidomide was found to activate the MDA5-mediated double-stranded RNA–sensing pathway in multiple myeloma cells, which led to ADAR1-regulated, interferon-mediated cell death. When ADAR1 was overexpressed, sensitivity to lenalidomide was reduced, and RNA editing was increased with suppression of the RNA-sensing pathways. In contrast, ADAR1 loss sensitized the myeloma cells to immunomodulatory drugs by activating these pathways and boosting interferon responses. Thus, if ADAR1 levels could be reduced, response to lenalidomide and other immunomodulatory drugs may be increased.
Clinical trials are already underway exploring the potential of CRBN E3 ligase modulators and new immunomodulatory drug analogues. ADAR1 inhibitors are also in preclinical development and may potentially be even more effective in combination with these novel approaches. The study investigators are also planning to further investigate the role of ADAR1 in alterative splicing in multiple myeloma for further impact on therapeutic strategies for overcoming immunomodulatory drug resistance in patients with multiple myeloma.
Disclosure: For full disclosures of the study authors, visit ashpublications.org.
