@misc{10481/107558,
year = {2025},
month = {9},
url = {https://hdl.handle.net/10481/107558},
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.},
organization = {MCIN/AEI/10.13039/501100011033 - ERDF (PID2021-126111OB-I00, PID2024-159252OB-I00)},
organization = {Spanish Association Against Cancer (LAB-AECC-2018; PROYE18012ROSE)},
organization = {Junta de Andalucía (PI-0203-2022, PI-0228-2024)},
organization = {University of Granada (B-CTS480-UGR20, C-EXP-051-UGR23, C-CTS-149-UGR23)},
organization = {Horizon 2020 Framework Programme (MSCA-IF-EF-RI 837897)},
organization = {Spanish Ministry of Science, Innovation, and Universities (FPU17/01258, FPU17/00067, FPU19/00576)},
organization = {Instituto de Salud Carlos III (PI22/01221)},
organization = {CIBERONC (CB16/12/00350)},
publisher = {Springer Nature},
title = {High-fidelity Cas9-mediated targeting of KRAS driver mutations restrains lung cancer in preclinical models},
doi = {10.1038/s41467-025-62350-4},
author = {Álvarez Pérez, Juan Carlos and Sanjuan Hidalgo, Juan and Arenas, Alberto M. and Hernández-Navas, Iván and Benítez Cantós, María Soledad and Andrades Delgado, Álvaro and Calabuig-Fariñas, Silvia and Jantus-Lewintre, Eloisa and Paz-Ares, Luis and Ferrer, Irene and Medina Vico, Pedro Pablo},
}