Selective targeting of point-mutated KRAS through artificial microRNAs

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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.

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Acunzo, M., Romano, G., Nigita, G., Veneziano, D., Fattore, L., Laganà, A., … Croce, C. M. (2017). Selective targeting of point-mutated KRAS through artificial microRNAs. Proceedings of the National Academy of Sciences of the United States of America, 114(21), E4203–E4212. https://doi.org/10.1073/pnas.1620562114

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