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Targeting oncogenic KRAS in non-small cell lung cancer with EGFR aptamer-conjugated multifunctional RNA nanoparticles
Linlin Yang1, Zhefeng Li2, Daniel W Binzel2
1Department of Radiation Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
Abstract:
KRAS mutations are one of the most common oncogenic driver mutations in human cancers, including non-small cell lung cancer (NSCLC), and have established roles in cancer pathogenesis and therapeutic resistance. The development of effective inhibitors of mutant KRAS represents a significant challenge. Three-way junction (3WJ)-based multi-functional RNA nanoparticles have the potential to serve as an effective in vivo siRNA delivery platform with the ability to enhance tumor targeting specificity and visualize biodistribution through an imaging moiety. Herein, we assembled novel EGFRapt-3WJ-siKRAS mutation targeted nanoparticles to target EGFR-expressing human NSCLC harboring a KRAS mutation to silence KRAS expression in a tumor cell-specific fashion. We found that EGFRapt-3WJ-siKRAS nanoparticles potently depleted cellular KRAS expression, resulting in attenuation of downstream MAPK pathway signaling, cell proliferation, migration/invasion ability, and sensitized NSCLC cells to chemoradiotherapy. In vivo, these nanoparticles induced tumor growth inhibition in KRAS NSCLC tumor xenografts. Together, this study suggests that the 3WJ pRNA-based platform has the potential to suppress mutant KRAS activity for the treatment of KRAS-driven human cancers, and warrants further development for clinical translation.
Insights
Novel RNA nanoparticles effectively silence KRAS mutations in non-small cell lung cancer (NSCLC) cells. This targeted approach inhibits tumor growth and enhances sensitivity to chemoradiotherapy, offering a promising strategy for KRAS-driven cancers.
Area of Science:
- Biotechnology
- Molecular Oncology
- Nanomedicine
Background:
- KRAS mutations are prevalent drivers in human cancers, including NSCLC, contributing to pathogenesis and therapeutic resistance.
- Targeting mutant KRAS remains a significant challenge in cancer therapy development.
Purpose of the Study:
- To develop and evaluate novel EGFR-targeted RNA nanoparticles for the specific delivery of siRNA to silence KRAS expression in NSCLC.
- To assess the efficacy of these nanoparticles in vitro and in vivo for potential clinical translation.
Main Methods:
- Assembly of three-way junction (3WJ)-based RNA nanoparticles functionalized with an EGFR aptamer (EGFRapt) and siRNA targeting KRAS (siKRAS).
- In vitro assessment of nanoparticle-mediated KRAS silencing, downstream signaling pathway inhibition (MAPK), and effects on cell proliferation, migration, and chemosensitization.
- In vivo evaluation of nanoparticle efficacy in NSCLC tumor xenografts.
Main Results:
- EGFRapt-3WJ-siKRAS nanoparticles effectively reduced cellular KRAS expression.
- Downstream MAPK signaling, cell proliferation, and migration/invasion were attenuated.
- NSCLC cells demonstrated increased sensitivity to chemoradiotherapy.
- In vivo studies showed significant tumor growth inhibition in KRAS-mutant NSCLC xenografts.
Conclusions:
- The 3WJ pRNA-based nanoparticle platform demonstrates potential for KRAS-specific gene silencing in NSCLC.
- These nanoparticles show promise for treating KRAS-driven cancers by suppressing mutant KRAS activity.
- Further development is warranted for clinical translation of this RNA nanoparticle-based therapeutic strategy.
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