High-fidelity Cas9-mediated targeting of KRAS driver mutations restrains lung cancer in preclinical models

Juan Carlos Álvarez-Pérez, Juan Sanjuán-Hidalgo, Alberto M. Arenas, Ivan Hernández-Navas, Maria S. Benitez‑Cantos, Alvaro Andrades, Silvia Calabuig-Fariñas, Eloisa Jantus-Lewintre, Luis Paz-Ares, Irene Ferrer and Pedro P. Medina ()
Additional contact information
Juan Carlos Álvarez-Pérez: Gene Expression Regulation and Cancer Group (CTS-993). GENYO. Centre for Genomics and Oncological Research: Pfizer-University of Granada-Andalusian Regional Government
Juan Sanjuán-Hidalgo: Gene Expression Regulation and Cancer Group (CTS-993). GENYO. Centre for Genomics and Oncological Research: Pfizer-University of Granada-Andalusian Regional Government
Alberto M. Arenas: Gene Expression Regulation and Cancer Group (CTS-993). GENYO. Centre for Genomics and Oncological Research: Pfizer-University of Granada-Andalusian Regional Government
Ivan Hernández-Navas: CIBERONC
Maria S. Benitez‑Cantos: Gene Expression Regulation and Cancer Group (CTS-993). GENYO. Centre for Genomics and Oncological Research: Pfizer-University of Granada-Andalusian Regional Government
Alvaro Andrades: Gene Expression Regulation and Cancer Group (CTS-993). GENYO. Centre for Genomics and Oncological Research: Pfizer-University of Granada-Andalusian Regional Government
Silvia Calabuig-Fariñas: Universitat de Valencia
Eloisa Jantus-Lewintre: Fundación para la Investigación del Hospital General Universitario de Valencia; CIBERONC
Luis Paz-Ares: H12O-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación Hospital 12 de Octubre (i+12) & Centro Nacional de Investigaciones Oncológicas (CNIO), CIBERONC, UCM
Irene Ferrer: CIBERONC
Pedro P. Medina: Gene Expression Regulation and Cancer Group (CTS-993). GENYO. Centre for Genomics and Oncological Research: Pfizer-University of Granada-Andalusian Regional Government

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Missense mutations in the 12th codon of KRAS are key drivers of lung cancer, with glycine-to-cysteine (G12C) and glycine-to-aspartic acid (G12D) substitutions being among the most prevalent. These mutations are strongly associated with poor survival outcomes. Given the critical role of KRAS in lung cancer and other cancers, it remains as a major target for the development of new and complementary treatments. We have developed a CRISPR-High Fidelity (HiFi)-Cas9-based therapy strategy that can effectively and specifically target KRASG12C and KRASG12D mutants, avoiding KRASWT off-targeting and affecting KRAS downstream pathways, thereby significantly reducing tumorgenicity. The delivery of HiFiCas9 components via ribonucleoprotein particles (RNPs) and adenovirus (AdV) effectively abrogates cell viability in KRAS-mutant Non-Small Cell Lung Cancer (NSCLC) preclinical models, including 2D and 3D cell cultures, cell-derived xenografts (CDX), and patient-derived xenograft organoids (PDXO). Our in vitro studies demonstrate that HiFiCas9-based therapy achieves superior KRAS inhibition compared to Sotorasib and effectively circumvents certain resistance mechanisms associated with Sotorasib treatment. Moreover, in vivo delivery using adenoviral particles significantly suppresses tumor growth in preclinical NSCLC models. Collectively, our findings establish HiFiCas9 as an effective therapeutic strategy with promising clinical applications, especially if in vivo delivery methods are further optimized.

Date: 2025
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DOI: 10.1038/s41467-025-62350-4

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