Silencing of Oncogenic KRAS by Mutant-Selective Small Interfering RNA
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Abstract
Oncogenic mutations in the KRAS gene are well-established drivers of cancer. While the recently developed KRASG12C inhibitors offer a targeted KRAS therapy and have shown success in the clinic, KRASG12C represents only 11% of all KRAS mutations. Current therapeutic approaches for all other KRAS mutations are both indirect and nonmutant-selective, largely focusing on inhibition of downstream KRAS effectors such as MAP kinases. Inhibition of KRAS downstream signaling results in a system-wide down-modulation of the respective targets, raising concerns about systemic cell toxicity. Here, we describe a custom short interfering RNA oligonucleotide (EFTX-D1) designed to preferentially bind mRNA of the most commonly occurring KRAS missense mutations in codons 12 and 13. We determined that EFTX-D1 preferentially reduced the mutant KRAS sequence versus wild-type at the levels of both transcription and translation and reversed oncogenic KRAS-induced morphologic and growth transformation. Furthermore, EFTX-D1 significantly impaired the proliferation of several KRAS mutant cancer cell lines in 2-D as well as 3-D assays. Taken together, our data indicate a novel use of RNA interference to target oncogenic KRAS-driven cancers specifically.
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Off-target effects are concerning for siRNA-based therapies, as siRNAs can bind mRNAs despite one or two sequence mismatches, which may lead to generalized cell toxicity even in healthy tissue.
“Off-target effects are concerning for siRNA-based therapies, as siRNAs can bind mRNAs despite one or two sequence mismatches, which may lead to generalized cell toxicity even in healthy tissue [66].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [66]
This siRNA had a higher affinity for the targeted oncogenic mutations than wildtype.
“This siRNA had a higher affinity for the targeted oncogenic mutations than wildtype [66].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [66]
Alternative KRAS siRNAs have been designed to exploit mismatch binding to increase mutant KRAS specificity, by creating siRNA sequences containing three mismatches against wildtype but only two mismatches against three KRAS mutants: G12C, G12D, and G13D.
“Alternative KRAS siRNAs have been designed to exploit mismatch binding to increase mutant KRAS specificity, by creating siRNA sequences containing three mismatches against wildtype but only two mismatches against three KRAS mutants: G12C, G12D, and G13D.”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [66]
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 [66]
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References 38 · Cited by 22
- Authors
- Papke, B., Azam, S. H., Feng, A. Y., Gutierrez-Ford, C., Huggins, H., Pallan, P. S., Van Swearingen, A. E. D., Egli, M., Cox, A. D., Der, C. J., & Pecot, C. V.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Vanderbilt University (US)
- University of North Carolina at Chapel Hill , , , ,
- Corresponding author
- Pecot, Chad V.
- ORCID
- Venue
- ACS Pharmacology & Translational Science
- Publisher
- American Chemical Society (ACS)
- Published
- 2021-02-04
- Volume
- 4
- Issue
- 2
- Pages
- 703-712
- ISSN
- 2575-9108 (ISSN-L)
- PMC
- PMC8033609
- OpenAlex
- W3128365238
- Cited by
- 22
- References
- 38
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 2 · 2023: 7 · 2022: 1 · 2021: 1
- FWCI
- 0.86
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- ACS Pharmacology & Translational Science (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Association for Cancer Research (15-90-25-DER)
- National Cancer Institute (1R41CA246848, P01CA203657, P50CA196510, R01CA175747, R01CA215075, R01CA223775, R01CA42978, R21CA179193, R35CA232113, U01CA199235)
- Free To Breathe
- Lustgarten Foundation (388222)
- Deutsche Forschungsgemeinschaft (DFG PA 3051/1-1)
- North Carolina Biotechnology Center
- U.S. Department of Defense (W81XWH15-1-0611)
- American Cancer Society (MRSG-14-222-01-RMC)
- Lung Cancer Research Foundation
- Volkswagen Foundation (Az 92 768)
- Stuart Scott V Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- KRAS, oncogenic KRAS mutations, siRNA, RNA interference, KRAS-driven cancers, tumor cell proliferation
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