Lenalidomide combined with miR-22 mimics may sensitize multiple myeloma (MM) cells to help overcome drug resistance, according to research published in Cancers.
MYC, a master regulator of MM, can drive deregulation of microRNAs and contributes to drug resistance in MM. MM remains an incurable disease, frequently because patients develop resistance to immunomodulatory imide drugs (IMiDs), including lenalidomide.
MYC has been shown to be upregulated in patients when they become refractory to lenalidomide. MYC also downregulates miRNA expression, and miRNA-22 repression is associated with poorer outcomes.
The study authors investigated the role of MYC on miRNA expression in MM and discovered an MYC-miR-22 feed-forward loop. Both miR-22 and MYC expression had an inverse correlation in MM based on analysis of 96 MM cell cases and 29 plasma cell leukemia cases.
Inhibiting MYC led to an increase in miR-22 levels in MM cells. The study authors found that treatment with lenalidomide led to an increase in miR-22, which occurred with MYC downregulation.
Based on analysis of MM data sets, the authors found that, when treated with IMiDs, patients who had high miR-22 and low MYC levels had better progression-free survival and had a lower risk of relapse.
“Based on these findings, we hypothesize that MYC-proficient MM cells downregulate miR-22 levels to amplify MYC-driven myelomagenesis by promoting cell survival and escape from NK cytotoxic activity,” the authors wrote in their report. “However, at the same time, these events make MM cells more vulnerable to increased expression of miR-22, which indeed triggers MYC-dependent synthetic lethality.”
The results suggest that lenalidomide combined with miR-22 mimics could be a potential therapeutic strategy in MM. MiR-22 levels may also help predict patients who respond better to IMiD-based therapy.
Caracciolo D, Riillo C, Juli G, et al. miR-22 modulates lenalidomide activity by counteracting MYC addiction in multiple myeloma. Cancers (Basel). 2021;13(17):4365. doi:10.3390/cancers13174365