Selective targeting of point-mutated KRAS through artificial microRNAs.

Proc Natl Acad Sci U S A 2017 05 8;114(21):E4203-E4212. Epub 2017 May 8.

Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210;

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.

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Source
http://dx.doi.org/10.1073/pnas.1620562114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448175PMC
May 2017
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