Abstract 4368: Selective targeting of oncogenic KRAS G12D using complementary peptide nucleic acid oligomers

KRAS is a proto-oncogene that has activating mutations in ∼15-30% of all cancers. Conventional therapies non-selectively target tumor and normal cells which may cause high toxicities, and programmable mutant-selective targeted inhibitors are lacking. Peptide nucleic acids (PNAs) have base sequences analogous to DNA, except they have modified peptide backbones instead of sugar-phosphate backbones, allowing them to hybridize with DNA with high avidity to suppress transcription. Here, we developed KRAS G12D-selective PNA oligomers with novel cell-penetrating peptides (CPP) flanking regions. Immunofluorescently labeled PNA-CPP oligomers had high uptake rates in cells and nuclei. Complementary PNA-CPP treatment resulted in repression of KRAS G12D RNA and protein expression within 2 hours, lasting up to 48 hours. Alternative end modifications and lengths of complementary KRAS sequence were tested using dose-response cell viability assays. These experiments identified modifications to PNA oligomer sequence composition and length that were most effective at selectively preventing growth of on-target KRAS G12D cells, while relatively sparing off-target KRAS G12C cells. These PNA-CPPs were effective against a panel of pancreatic ductal adenocarcinoma cell lines and patient derived xenografts in vivo. These results indicate that PNA-CPPs show promise as both a tool for studying tumors driven by oncogenic point mutations, and as a possible therapeutic strategy capable of sparing normal cells while selectively targeting mutant cancer cells. Citation Format: Jayati Mondal, Dennis Lam, Mary E. Gerritsen, Tilmann M. Brotz, Jodi G. Kennedy, Bruce Rehlaender, Arthur J. Ross, Daniel E. Levy, Christopher A. Bonagura, William Lanzilotta, Frank McCormick, Jeffrey H. Rothman, Andrew L. Wolfe. Selective targeting of oncogenic KRAS G12D using complementary peptide nucleic acid oligomers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4368.