Development of siRNA payloads to target KRAS-mutant cancer

Yuan, T. L., Fellmann, C., Lee, C. S., Ritchie, C. D., Thapar, V., Lee, L. C., Hsu, D. J., Grace, D., Carver, J. O., Zuber, J., Luo, J., McCormick, F., Lowe, S. W. (August 2014) Development of siRNA payloads to target KRAS-mutant cancer. Cancer Discovery, 4 (10). p. 1182. ISSN 21598274

URL: http://www.ncbi.nlm.nih.gov/pubmed/25100204
DOI: 10.1158/2159-8290.cd-13-0900

Abstract

RNA interference (RNAi) is a powerful tool for target identification and can lead to novel therapies for pharmacologically intractable targets such as KRAS. RNAi therapy must combine potent siRNA payloads with reliable in vivo delivery for efficient target inhibition. We employed a functional "Sensor" assay to establish a library of potent siRNAs against RAS pathway genes and show they efficiently suppress their targets at low dose. This reduces off-target effects and enables combination gene knockdown. We administered Sensor siRNAs in vitro and in vivo and validated the delivery of KRAS siRNA alone and siRNA targeting the complete RAF effector node (A/B/C-RAF) as promising strategies to treat KRAS-mutant colorectal cancer. We further demonstrate that improved therapeutic efficacy is achieved by formulating siRNA payloads that combine both single-gene siRNA and node-targeted siRNAs (KRAS+PIK3C-A/B). The customizable nature of Sensor siRNA payloads offers a universal platform for combination target identification and development of RNAi therapeutics.

Item Type: Paper
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > siRNA
CSHL Authors:
Communities: CSHL labs > Lowe lab
Depositing User: Matt Covey
Date: 6 August 2014
Date Deposited: 15 Aug 2014 15:26
Last Modified: 24 May 2016 19:39
PMCID: PMC4184972
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30687

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