Therapeutic Silencing of KRAS using Systemically Delivered siRNAs
Menée in vitro et in vivo, cette étude évalue l'intérêt d'utiliser des petits ARNs interférents, acheminés à l'intérieur des cellules tumorales par des nanoparticules, pour développer des thérapies ciblant l'expression du gène KRAS
Despite being amongst 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 anti-proliferative effects of KRAS silencing in vitro. For in vivo experiments, we used a nano-liposomal delivery platform, DOPC, for systemic delivery of siRNAs. Various lung and colon cancer models were utilized to determine efficacy of systemic KRAS siRNA based on tumor growth, development of metastasis and down-stream signaling. KRAS siRNA sequences induced >90% knock-down 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, while significant increases in caspase-3 activity was 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.
http://mct.aacrjournals.org/content/early/2014/10/03/1535-7163.MCT-14-0074.abstract