The DOI matches its Crossref record; 38 of the 39 references it cites were found in a registry or an index.
Development of siRNA Payloads to Target KRAS -Mutant Cancer
Open accessPublished version of a preprint
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 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]
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Citations
Cites
Bartel (2004) · doi:10.1016/s0092-8674(04)00045-5 · Cited by 34,714
Hannon, G. J. (2002) · Nature · doi:10.1038/418244a · Cited by 3,651
Hopkins, A. L., & Groom, C. R. (2002) · Nature Reviews Drug Discovery · doi:10.1038/nrd892 · Cited by 3,305 · cited 1×
“RNAi can, in principle, be applied to reversibly silence any target gene [reviewed in (8, 9)], thereby increasing the druggable landscape from 10% to virtually 100% of the genome (10, 11).”
BackgroundEvidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles
Davis, M. E., Zuckerman, J. E., Choi, C. H. J., Seligson, D. B., Tolcher, A. W., Alabi, C. A., Yen, Y., Heidel, J. D., & Ribas, A. (2010) · Nature · doi:10.1038/nature08956 · Cited by 2,541 · cited 2×
“Sensor siRNAs can be effectively delivered in vivo To test the therapeutic efficacy of Sensor siRNAs in vivo, we used previously characterized cyclodextrin-polymer nanoparticles (29, 30) to deliver Sensor siRNAs to tumors in mice.”
BackgroundMethodExpression profiling reveals off-target gene regulation by RNAi
Jackson, A. L., Bartz, S. R., Schelter, J., Kobayashi, S. V., Burchard, J., Mao, M., Li, B., Cavet, G., & Linsley, P. S. (2003) · Nature Biotechnology · doi:10.1038/nbt831 · Cited by 2,370
RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF
Poulikakos, P. I., Zhang, C., Bollag, G. E., Shokat, K. M., & Rosen, N. X. (2010) · Nature · doi:10.1038/nature08902 · Cited by 1,841 · cited 2×
“In comparison, the small molecule BRAF inhibitor PLX4720 did not inhibit the proliferation of KRAS-mutant cells (Figure 4B), as previously reported (2, 3, 26).”
BackgroundResultRAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth
Hatzivassiliou, G., Song, K. W., Yen, I., Brandhuber, B. J., Anderson, D. J., Alvarado, R., Ludlam, M. J. C., Stokoe, D., Gloor, S. L., Vigers, G. P. A., et al. (2010) · Nature · doi:10.1038/nature08833 · Cited by 1,649 · cited 2×
“In comparison, the small molecule BRAF inhibitor PLX4720 did not inhibit the proliferation of KRAS-mutant cells (Figure 4B), as previously reported (2, 3, 26).”
BackgroundResultKinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF
Heidorn, S. J., Milagre, C. S., Whittaker, S. R., Nourry, A., Niculescu‐Duvaz, I., Dhomen, N. S., Hussain, J., Reis-Filho, J. S., Springer, C. J., Pritchard, C. A., et al. (2010) · Cell · doi:10.1016/j.cell.2009.12.040 · Cited by 1,497 · cited 2×
“This finding is consistent with recent reports that CRAF plays a critical role in RAS-driven lung carcinoma and melanoma (24-26).”
ResultRas oncogenes: split personalities
Karnoub, A. E., & Weinberg, R. A. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2438 · Cited by 1,467 · cited 1×
“Many KRAS effectors, including RAF, PI3K, RAL and RAC, have RAS-independent means of activation (36), which can be circumvented through direct targeting of effector nodes in addition to KRAS.”
BackgroundAltered cell cycle arrest and gene amplification potential accompany loss of wild-type p53
Livingstone, L. R., White, A., Sprouse, J., Livanos, E., Jacks, T., & Tlsty, T. D. (1992) · Cell · doi:10.1016/0092-8674(92)90243-6 · Cited by 1,328 · cited 9×
“Trp53 -/-MEFs (21) were grown in DMEM supplemented with 10% FBS. KRAS -/-MEFs were obtained from Dr. Mariano Barbacid (CNIO).”
BackgroundMethodInfluential
Cited by
Sorted by citations
Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer
Kamerkar, S., LeBleu, V. S., Sugimoto, H., Yang, S., Ruivo, C. F., Melo, S. A., Lee, J. J., & Kalluri, R. (2017) · Nature · doi:10.1038/nature22341 · Cited by 2,639
RAS Proteins and Their Regulators in Human Disease
Simanshu, D. K., Nissley, D. V., & McCormick, F. (2017) · Cell · doi:10.1016/j.cell.2017.06.009 · Cited by 1,943
Self-citationRAS isoforms and mutations in cancer at a glance
Hobbs, G. A., Der, C. J., & Rossman, K. L. (2016) · Journal of Cell Science · doi:10.1242/jcs.182873 · Cited by 973
“…metabolism), (v) unbiased genetic or chemical screens for synthetic lethal interactors (Barbie et al., 2009; Kumar et al., 2012; Luo et al., 2009; Sarthy et al., 2007; Scholl et al., 2009) and (vi) RNA interference (RNAi) of KRAS expression (Pecot et al., 2014; Xue et al., 2014; Yuan et al., 2014).”
BackgroundRole of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer
Buscail, L., Bournet, B., & Cordelier, P. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0245-4 · Cited by 721
Genetics and biology of pancreatic ductal adenocarcinoma
Ying, H., Dey, P., Yao, W., Kimmelman, A. C., Draetta, G. F., Maitra, A., & DePinho, R. A. (2016) · Genes & Development · doi:10.1101/gad.275776.115 · Cited by 527
Metadata
- 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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