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Published on: June 28, 2013
U1 Adaptors Suppress the KRAS-MYC Oncogenic Axis in Human Pancreatic Cancer Xenografts
Ashley T Tsang1,2, Crissy Dudgeon1,2, Lan Yi2
1Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.
Abstract:
Targeting KRAS and MYC has been a tremendous challenge in cancer drug development. Genetic studies in mouse models have validated the efficacy of silencing expression of both KRAS and MYC in mutant KRAS-driven tumors. We investigated the therapeutic potential of a new oligonucleotide-mediated gene silencing technology (U1 Adaptor) targeting KRAS and MYC in pancreatic cancer. Nanoparticles in complex with anti-KRAS U1 Adaptors (U1-KRAS) showed remarkable inhibition of KRAS in different human pancreatic cancer cell lines in vitro and in vivo As a nanoparticle-free approach is far easier to develop into a drug, we refined the formulation of U1 Adaptors by conjugating them to tumor-targeting peptides (iRGD and cRGD). Peptides coupled to fluorescently tagged U1 Adaptors showed selective tumor localization in vivo Efficacy experiments in pancreatic cancer xenograft models showed highly potent (>90%) antitumor activity of both iRGD and (cRGD)2-KRAS Adaptors. U1 Adaptors targeting MYC inhibited pancreatic cancer cell proliferation caused by apoptosis in vitro (40%-70%) and tumor regressions in vivo Comparison of iRGD-conjugated U1 KRAS and U1 MYC Adaptors in vivo revealed a significantly greater degree of cleaved caspase-3 staining and decreased Ki67 staining as compared with controls. There was no significant difference in efficacy between the U1 KRAS and U1 MYC Adaptor groups. Our results validate the value in targeting both KRAS and MYC in pancreatic cancer therapeutics and provide evidence that the U1 Adaptor technology can be successfully translated using a nanoparticle-free delivery system to target two undruggable genes in cancer. Mol Cancer Ther; 16(8); 1445-55. ©2017 AACR.
Insights
New U1 Adaptor technology effectively silences KRAS and MYC genes in pancreatic cancer models. This nanoparticle-free approach shows potent antitumor activity, validating dual gene targeting for difficult-to-treat cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Targeting KRAS and MYC oncogenes is challenging in cancer therapy.
- Genetic studies support KRAS and MYC silencing for mutant KRAS-driven tumors.
Purpose of the Study:
- Investigate U1 Adaptor gene silencing technology for KRAS and MYC in pancreatic cancer.
- Evaluate nanoparticle-free delivery systems for therapeutic translation.
Main Methods:
- Developed U1 Adaptors targeting KRAS and MYC.
- Conjugated U1 Adaptors to tumor-targeting peptides (iRGD, cRGD).
- Assessed efficacy in pancreatic cancer cell lines and xenograft models in vitro and in vivo.
Main Results:
- U1-KRAS Adaptors significantly inhibited KRAS in vitro and in vivo.
- Peptide-conjugated U1 Adaptors showed selective tumor localization.
- Both iRGD and (cRGD)2-KRAS Adaptors demonstrated >90% antitumor activity.
- U1 MYC Adaptors induced apoptosis and tumor regression.
- No significant efficacy difference between U1 KRAS and U1 MYC Adaptors.
Conclusions:
- Dual targeting of KRAS and MYC is validated for pancreatic cancer therapeutics.
- U1 Adaptor technology is a viable nanoparticle-free delivery system for targeting previously undruggable genes.
- This approach holds promise for developing novel pancreatic cancer treatments.
