期刊
MOLECULAR CANCER THERAPEUTICS
卷 13, 期 12, 页码 2876-2885出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-14-0074
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资金
- NIH [CA016672, CA109298, P50 CA083639, P50 CA098258, CA128797, U54 CA151668, CA177909, U24CA143835, CA172670, R01CA157880, DOD CA100879]
- Cancer Prevention Research Institute of Texas [RP110595]
- Ovarian Cancer Research Fund, Inc. (Program Project Development Grant)
- Department of Defense [OC073399, W81XWH-10-1-0158]
- RGK Foundation
- Gilder Foundation
- Blanton-Davis Ovarian Cancer Research Program
- Betty Anne Asche Murray Distinguished Professorship
- NCI (T32 training grant) [CA009666]
- Conquer Cancer Foundation ASCO Young Investigator Award
- Ben F. Love Fellowship in Innovative Cancer Therapies
- Jeffrey Lee Cousins Fellowship in Lung Cancer Research
- DoCM Advanced Scholar Program
- Ovarian Cancer Research Funds
- Foundation for Women's Cancer
- Cancer Prevention Research Institute of Texas training grants [RP101502, RP101489]
- National Institute of General medical Sciences [5T32 GM007092]
- William C. Liedtke, Jr., Chair in Cancer Research
Despite being among the most common oncogenes in human cancer, to date, there are no effective clinical options for inhibiting KRAS activity. We investigated whether systemically delivered KRAS siRNAs have therapeutic potential in KRAS-mutated cancer models. We identified KRAS siRNA sequences with notable potency in knocking down KRAS expression. Using lung and colon adenocarcinoma cell lines, we assessed antiproliferative effects of KRAS silencing in vitro. For in vivo experiments, we used a nanoliposomal delivery platform, DOPC, for systemic delivery of siRNAs. Various lung and colon cancer models were used to determine efficacy of systemic KRAS siRNA based on tumor growth, development of metastasis, and downstream signaling. KRAS siRNA sequences induced >90% knockdown of KRAS expression, significantly reducing viability in mutant cell lines. In the lung cancer model, KRAS siRNA treatment demonstrated significant reductions in primary tumor growth and distant metastatic disease, while the addition of CDDP was not additive. Significant reductions in Ki-67 indices were seen in all treatment groups, whereas significant increases in caspase-3 activity were only seen in the CDDP treatment groups. In the colon cancer model, KRAS siRNA reduced tumor KRAS and pERK expression. KRAS siRNAs significantly reduced HCP1 subcutaneous tumor growth, as well as outgrowth of liver metastases. Our studies demonstrate a proof-of-concept approach to therapeutic KRAS targeting using nanoparticle delivery of siRNA. This study highlights the potential translational impact of therapeutic RNA interference, which may have broad applications in oncology, especially for traditional undruggable targets. (C) 2014 AACR.
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