Mutant KRAS is a druggable target for pancreatic cancer
Open accessAbstract
Significance: Pancreatic cancer is still one of the major challenges in clinical oncology. Mutant KRAS is a driving oncogene in the majority of human pancreatic cancer cases. We have made an effort to meet this challenge by developing a therapeutic platform for local and prolonged delivery of siRNA. Our results show that the siRNA targeted against KRAS mutations with a local prolonged release system knocks down KRAS expression in vitro and in vivo, leading to an antitumor effect. Our report describes an applicable and efficient delivery method of siRNA that overcomes the major obstacles of toxicity and organ accessibility. Notably our approach enabled the conversion of KRAS from a nondruggable to a potentially druggable cancer target.
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Other siRNAs have been designed to specifically target KRAS G12D, such as siG12D-LODER, which is in clinical trials against KRAS G12D-driven pancreatic cancer.
“Other siRNAs have been designed to specifically target KRAS G12D, such as siG12D-LODER, which is in clinical trials against KRAS G12D-driven pancreatic cancer [70].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [70]
The section on LODER-derived siG12D identifies it as an siRNA directed against mutant KRAS G12D, and the in-vivo results describe its effects in pancreatic tumor models. The passages in our copy do not establish that siG12D-LODER was in clinical trials; the reported tests are in cells and animals. Page numbers were not provided. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAcute silencing of KRAS via RNAi or CRISPR in KRAS mutant pancreatic cancer cells results in cell cycle arrest, apoptosis, and suppression of anchorage-independent proliferation in vitro, and attenuated tumor growth and metastasis in xenograft models.
“In KRAS mutant pancreatic cancer cells, acute silencing of KRAS via RNAi or CRISPR results in cell cycle arrest, apoptosis and suppression of anchorage-independent proliferation in vitro, and attenuated tumor growth and metastasis in xenograft models (66–68).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [67]
Silencing mutant KRAS down-regulates activity of multiple Ras effector pathways including MAPK and PI3K.
“Silencing mutant KRAS down-regulates the activity of multiple Ras effector pathways including the MAPK and PI3K pathways (67, 68).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [67]
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- Authors
- Zorde Khvalevsky, E., Gabai, R., Rachmut, I. H., Horwitz, E., Brunschwig, Z., Orbach, A., Shemi, A., Golan, T., Domb, A. J., Yavin, E., Giladi, H., Rivkin, L., Simerzin, A., Eliakim, R., Khalaileh, A., Hubert, A., Lahav, M., Kopelman, Y., Goldin, E., Dancour, A., Hants, Y., Arbel-Alon, S., Abramovitch, R., Shemi, A., & Galun, E.
- Affiliations
- Silenseed LTD, and
- Tel Aviv University (IL)
- Hebrew University of Jerusalem (IL)
- Sheba Medical Center (IL)
- Department of Surgery,
- Sharett Institute of Oncology,
- Gastroenterology Institute, and
- Shaare Zedek Medical Center (IL)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-12-02
- Volume
- 110
- Issue
- 51
- Pages
- 20723-20728
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3870687
- OpenAlex
- W2135500767
- Cited by
- 295
- References
- 23
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 17 · 2023: 27 · 2022: 28 · 2021: 31 · 2020: 23 · 2019: 20 · 2018: 29 · 2017: 27 · 2016: 29 · 2015: 32 · 2014: 9
- FWCI
- 10.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- pancreatic ductal adenocarcinoma, KRAS mutation, siRNA delivery, RNA interference, sustained drug release, epithelial-mesenchymal transition, tumor growth inhibition, therapeutic target
- MeSH terms
- Animals, Drug Evaluation, Preclinical, Female, Humans, Mutation, Pancreatic Neoplasms, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), Drug Delivery Systems, Mice, SCID, ras Proteins, Absorbable Implants, Gene Silencing, Carcinoma, Pancreatic Ductal, RNA, Small Interfering, Cell Line, Tumor, Cell Proliferation, Mice
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