Targeting KRAS Mutant Genes with ADGN-123 and ADGN-121 Nanoparticles: Overcoming Resistance to Small Molecule Inhibitors

Recent advancements have led to the approval of KRAS G12C inhibitors, such as sotorasib and adagrasib, and the development of MTRX-1133 for KRAS G12D mutations. However, the effectiveness of these treatments is hindered by adaptive resistance mechanisms, including the development of secondary KRAS mutations and the activation of compensatory pathways. To address this challenge, a novel approach combining gene editing with tumor-targeted nanoparticles has been devised. Specifically, gene-editing complexes ADGN-123 and ADGN-121, which contain sgRNAs and proprietary peptides, were designed to target KRAS G12C and G12D mutations, respectively. These complexes were tested on various cancer cell lines, including those with acquired resistance to existing inhibitors and secondary KRAS mutations.
In the study, ADGN-123 demonstrated the ability to suppress cell proliferation and ERK phosphorylation in cells with KRAS G12C mutations, including those with secondary mutations or a permanently active KRAS state. Similarly, ADGN-121 effectively inhibited the proliferation of cells with high levels of KRAS G12D-GTP. Notably, no resistance was observed following treatments with either complex. The in vivo efficacy of ADGN-121 was assessed in a mouse model with PANC-1 (KRAS G12D) xenografts, where it significantly reduced tumor growth in a dose-dependent manner after just two intravenous administrations.
The ADGN treatments were found to be well-tolerated, with no clinical toxicity observed. This research establishes a promising strategy for targeting cancer driver mutations in vivo, leading to substantial tumor regression and providing a potent alternative to traditional small molecule inhibitors of KRAS G12C and G12D.