In this article, we provided a novel concept that microRNA can be used as a therapeutic strategy to precisely target oncogene mutation-driven cancers, in our case, it is NRAS. NRAS is long considered an undruggable oncogene because of the lack of deep hydrophobic pockets on the catalytic G domain, the high binding affinity to GTP, and identical G domains among different RAS isoforms. In our study, we identified miR-708 can target and deplete NRAS expressions directly by targeting 3’UTR of NRAS mRNA in NRAS mutated cancer cells, resulting in the significant inhibition of cell proliferation, cell survival, anchorage-independent cell growth, and promotion of reactive oxygen species-induced apoptosis. On the other hand, cell proliferation is not disturbed by miRNA-708 in cells carrying wild-type NRAS. Therefore, our approach provides new insights that using microRNA to overcome the limitation of small molecule- or protein-based drugs to target those traditionally inaccessible mutated proteins. By demonstrating that miR-708 can effectively suppress NRAS in multiple NRAS-mutated cancer lines, we offer an opportunity of using miRNAs as the precision medicine for oncogene mutation-driven cancers.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0284744
