Abstract 7236: Selective deletion of the KRAS mutant gene with ADGN-123 and ADGN-121 peptide-RNA nanoparticles: A new strategy to overcome acquired resistance to KRASG12C and KRASG12D small molecule inhibitors
Authors: Divita Gilles , Grunenberger Audrey , Guzman-gonzalez Veronica , Czuba Elodie , Boularache Khadidja , Guidetti Melanie , Josserand Veronique , Desai Neil 
Published: March 2024

Abstract
KRAS codon12 mutations are among the most commonly observed mutations in cancers. Recently, KRASG12C inhibitors (sotorasib and adagrasib) have been approved and KRASG12D inhibitor MTRX-1133 has shown preclinical efficacy in KRASG12D mutated cancers. However, these inhibitors are limited by adaptive resistance, mainly associated with the emergence of secondary KRAS mutations, activation of feedback pathway and amplification of KRASG12C allele. We have developed a new potent strategy combining gene editing with tumor selective peptide nanoparticles, to overcome acquired resistance to KRASG12C and KRASG12D inhibitors.
ADGN-123 and ADGN-121 are gene-editing complexes containing proprietary sgRNA targeting KRASG12C and KRASG12D respectively, complexed with proprietary peptides. ADGN-123 and ADGN-121 were evaluated on pancreas, colorectal, and lung cancer cells harboring KRASG12C or G12D mutations. ADGN-123 was evaluated on NCI-H358 and Mia-PACA generated clones resistant to sotorasib/adagrasib and harboring KRASG12C,R68M and KRASG12C,Y96D secondary mutations. ADGN-121 was evaluated on ASPC-1 and PANC-1 generated clones resistance to MRTX-1133. In-vivo efficacy of IV-administered ADGN-121 (0.25-1.0 mg/kg, day 1 and 7) was evaluated in PANC-1 (KRASG12D) mouse xenografts.
ADGN-123 and ADGN-121 selectively silenced KRASG12C and KRASG12D, respectively, in cancer cells resulting in inhibition of cell proliferation (IC50: 10-30 nM) and of the phosphorylation of ERK and AKT. we showed that ADGN-123 containing gRNAG12C/mRNACas9 blocks the proliferation (IC50 : 10-20 nM) of cells with secondary KRASG12C/R68M and KRASG12C/Y96D mutations or with KRAS in a permanent active state and effectively inhibits ERK phosphorylation. We showed that ADGN-121 containing gRNAG12D/mRNACas9 can effectively inhibit the proliferation (IC50 : 10-15 nM) of ASPC-1 MRTX-1133R and PANC-1 MRTX-1133R cells with high level of KRASG12D-GTP active state. No resistance was detected after ADGN-123 or ADGN-121 treatments. We demonstrated that only two IV-administrations of ADGN-121 containing gRNAG12D/mRNACas9 abolished PANC-1 tumor growth in a dose dependent manner, resulting in significant tumor regression at 1.0 mg/kg. In contrast, no effect on tumor growth was observed with nonspecific gRNA. ADGN treatments were well tolerated, with no signs of clinical toxicity detected after single or repeat administration.
Our study provides a proof-of-concept that ADGN complexes can be applied to target driver mutations of cancers in vivo and permanently disrupt the oncogenic alleles, leading to major tumor regression. ADGN-123 and ADGN-121 constitute a potent alternative strategy to overcome resistance associated to small molecule inhibitors of KRASG12C and KRASG12D
Citation Format: Gilles Divita, Audrey Grunenberger, Veronica Guzman-gonzalez, Elodie Czuba, Khadidja Boularache, Melanie Guidetti, Veronique Josserand, Neil Desai. Selective deletion of the KRAS mutant gene with ADGN-123 and ADGN-121 peptide-RNA nanoparticles: A new strategy to overcome acquired resistance to KRASG12C and KRASG12D small molecule inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7236.