Development of siRNA Payloads to Target KRAS -Mutant Cancer
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Abstract
UNLABELLED: 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 used a functional "Sensor" assay to establish a library of potent siRNAs against RAS pathway genes and to show that 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/CRAF) 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 + PIK3CA/B). The customizable nature of Sensor siRNA payloads offers a universal platform for the combination target identification and development of RNAi therapeutics. SIGNIFICANCE: To advance RNAi therapy for KRAS-mutant cancer, we developed a validated siRNA library against RAS pathway genes that enables combination gene silencing. Using an in vivo model for real-time siRNA delivery tracking, we show that siRNA-mediated inhibition of KRAS as well as RAF or PI3K combinations can impair KRAS-mutant colorectal cancer in xenograft models.
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Each siRNA is processed by the endogenous RNA-induced silencing complex prior to binding to the target RNA, thereby inhibiting translation and promoting mRNA degradation.
“Each siRNA is then processed by the endogenous RNA-induced silencing complex prior to binding to the target RNA, in this case, KRAS, thereby inhibiting translation and promoting mRNA degradation [66,67,68].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [67]
The Results section on off-target effects says siRNAs are loaded into RISC, and the Results section on siKRAS-treated tumors reports reduced KRAS protein. Our copy does not specify that RISC processes each siRNA before target binding or that the resulting silencing occurs through both translation inhibition and mRNA degradation. No page numbers are available in our copy. (LLM, conf=0.83)
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- Authors
- 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.
- Affiliations
- University of California, San Francisco (US)
- Cold Spring Harbor Laboratory (US)
- National Cancer Institute (US)
- Memorial Sloan Kettering Cancer Center (US)
- Research Institute of Molecular Pathology (AT)
- Corresponding author
- Luo, Ji
- McCormick, Frank
- Lowe, Scott W.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2014-09-30
- Volume
- 4
- Issue
- 10
- Pages
- 1182-1197
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC4184972
- OpenAlex
- W2098360608
- Cited by
- 113
- References
- 39
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 8 · 2023: 7 · 2022: 12 · 2021: 8 · 2020: 10 · 2019: 12 · 2018: 9 · 2017: 12 · 2016: 12 · 2015: 9 · 2014: 1
- FWCI
- 4.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- U.S. Public Health Service (1ZIABC011437)
- National Cancer Institute (ZIABC011437, U01CA168409, U01CA168370, T32CA108462, P01CA013106, P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- siRNA, KRAS mutation, RNAi therapeutics, siRNA delivery, siRNA library, Ras signaling, Raf-1, PIK3CA, PIK3CB, colorectal cancer, off-target effects, xenograft models
- MeSH terms
- Animals, Disease Models, Animal, Humans, Mutation, Neoplasms, Genes, ras, Reproducibility of Results, Signal Transduction, Gene Library, Cluster Analysis, Drug Delivery Systems, Gene Transfer Techniques, Phosphatidylinositol 3-Kinases, Gene Expression Profiling, Xenograft Model Antitumor Assays, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, Tumor Burden, Mice, Nanoparticles, Gene Knockdown Techniques
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