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

doi:10.1073/pnas.1620562114

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

Istituto Nazionale Tumori Fondazione G. Pascale

Research output: Contribution to journal › Article › peer-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 language	English
Pages (from-to)	E4203-E4212
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	114
Issue number	21
DOIs	https://doi.org/10.1073/pnas.1620562114
Publication status	Published - May 23 2017

Keywords

Artificial microRNA
KRAS
RNAi

ASJC Scopus subject areas

General

Access to Document

10.1073/pnas.1620562114

Fingerprint Dive into the research topics of 'Selective targeting of point-mutated KRAS through artificial microRNAs'. Together they form a unique fingerprint.

Cite this

Acunzo, M., Romano, G., Nigita, G., Veneziano, D., Fattore, L., Laganà, A., Zanesi, N., Fadda, P., Fassan, M., Rizzotto, L., Kladney, R., Coppola, V., & 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

Selective targeting of point-mutated KRAS through artificial microRNAs. / Acunzo, Mario; Romano, Giulia; Nigita, Giovanni; Veneziano, Dario; Fattore, Luigi; Laganà, Alessandro; Zanesi, Nicola; Fadda, Paolo; Fassan, Matteo; Rizzotto, Lara; Kladney, Raleigh; Coppola, Vincenzo; Croce, Carlo M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 21, 23.05.2017, p. E4203-E4212.

Research output: Contribution to journal › Article › peer-review

Acunzo, M, Romano, G, Nigita, G, Veneziano, D, Fattore, L, Laganà, A, Zanesi, N, Fadda, P, Fassan, M, Rizzotto, L, Kladney, R, Coppola, V & Croce, CM 2017, 'Selective targeting of point-mutated KRAS through artificial microRNAs', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 21, pp. E4203-E4212. https://doi.org/10.1073/pnas.1620562114

Acunzo, Mario ; Romano, Giulia ; Nigita, Giovanni ; Veneziano, Dario ; Fattore, Luigi ; Laganà, Alessandro ; Zanesi, Nicola ; Fadda, Paolo ; Fassan, Matteo ; Rizzotto, Lara ; Kladney, Raleigh ; Coppola, Vincenzo ; Croce, Carlo M. / Selective targeting of point-mutated KRAS through artificial microRNAs. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 21. pp. E4203-E4212.

@article{950c62f08f3d4da5b7d92b8b412a22c8,

title = "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.",

keywords = "Artificial microRNA, KRAS, RNAi",

author = "Mario Acunzo and Giulia Romano and Giovanni Nigita and Dario Veneziano and Luigi Fattore and Alessandro Lagan{\`a} and Nicola Zanesi and Paolo Fadda and Matteo Fassan and Lara Rizzotto and Raleigh Kladney and Vincenzo Coppola and Croce, {Carlo M.}",

year = "2017",

month = may,

day = "23",

doi = "10.1073/pnas.1620562114",

language = "English",

volume = "114",

pages = "E4203--E4212",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "21",

}

TY - JOUR

T1 - Selective targeting of point-mutated KRAS through artificial microRNAs

AU - Acunzo, Mario

AU - Romano, Giulia

AU - Nigita, Giovanni

AU - Veneziano, Dario

AU - Fattore, Luigi

AU - Laganà, Alessandro

AU - Zanesi, Nicola

AU - Fadda, Paolo

AU - Fassan, Matteo

AU - Rizzotto, Lara

AU - Kladney, Raleigh

AU - Coppola, Vincenzo

AU - Croce, Carlo M.

PY - 2017/5/23

Y1 - 2017/5/23

N2 - 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.

AB - 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.

KW - Artificial microRNA

KW - KRAS

KW - RNAi

UR - http://www.scopus.com/inward/record.url?scp=85019631500&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019631500&partnerID=8YFLogxK

U2 - 10.1073/pnas.1620562114

DO - 10.1073/pnas.1620562114

M3 - Article

AN - SCOPUS:85019631500

VL - 114

SP - E4203-E4212

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 21

ER -