Selective targeting of point-mutated KRAS through artificial microRNAs

Mario Acunzo, Giulia Romano, Giovanni Nigita, Dario Veneziano, Luigi Fattore, Alessandro Laganà, Nicola Zanesi, Paolo Fadda, Matteo Fassan, Lara Rizzotto, Raleigh Kladney, Vincenzo Coppola, Carlo M. Croce

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)E4203-E4212
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number21
DOIs
Publication statusPublished - May 23 2017

Keywords

  • Artificial microRNA
  • KRAS
  • RNAi

ASJC Scopus subject areas

  • General

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