Targeting oncogenic KRAS in non-small cell lung cancer with EGFR aptamer-conjugated multifunctional RNA nanoparticles
Linlin Yang, Zhefeng Li, Daniel W. Binzel, Peixuan Guo, Terence M. Williams
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 EGFR apt -3WJ-si KRAS G12C mutation targeted nanoparticles to target EGFR-expressing human NSCLC harboring a KRAS G12C mutation to silence KRAS G12C expression in a tumor cell-specific fashion. We found that EGFR apt -3WJ-si KRAS G12C nanoparticles potently depleted cellular KRAS G12C 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 G12C 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.