Selective targeting of point-mutated KRAS through artificial microRNAs

Abstract

Mutated protein-coding genes drive the molecular pathogenesis of many diseases, including cancer. Specifically, mutated KRAS is a documented driver for malignant transformation, occurring early during the pathogenesis of cancers such as lung and pancreatic adenocarcinomas. Therapeutically, the indiscriminate targeting of wild-type and point-mutated transcripts represents an important limitation. Here, we leveraged on the design of miRNA-like artificial molecules (amiRNAs) to specifically target point-mutated genes, such as KRAS, without affecting their wild-type counterparts. Compared with an siRNA-like approach, the requirement of perfect complementarity of the microRNA seed region to a given target sequence in the microRNA/target model has proven to be a more efficient strategy, accomplishing the selective targeting of point-mutated KRAS in vitro and in vivo

Extracellular Vesicles and Epigenetic Modifications Are Hallmarks of Melanoma Progression

“…Finally, a major unmet issue in melanoma is targeting mutated forms of NRAS kinases, which are still considered undruggable. Thus, alternative strategies including siRNAs and artificial-miRNAs (amiRs) have been proposed for directly inhibiting the downstream transduction of specific RAS point-mutations [112,113]. Innovative nano-carriers are currently under investigation as a possible system for the selective delivery of these molecules into cancer cells [114,115].…”

CHAPTER 14. Strategies for Safe and Targeted Delivery of MicroRNA Therapeutics

“…through computational analysis, artificially generated miRNAs can be engineered that selectively target genes with single nucleotide mutations that contribute to the tumorigenic phenotype without affecting the wild-type gene. 168 this method can be expanded to designing miRNAs that selectively target genes only involved in pathology of the disease while eliminating targeting of irrelevant genes, thus preventing side-effects associated with unwanted targeting. An algorithm that may be useful for predicting such designer miRNAs is miRBooking.…”

The Butterfly Effect of RNA Alterations on Transcriptomic Equilibrium

“…Point mutations in miRNA target genes can be harnessed to develop powerful, targeted cancer therapies. Acunzo et al [60] devised miRNA-like artificial molecules (amiRNAs) and showed that amiR-KS3 specifically targets mutant KRAS transcripts carrying the G12S mutation without affecting wild-type transcripts in NSCLC. This amiR-KS3 treatment was also found to be effective in other cancers associated with G12S mutation.…”