2026-04-29T23:03:51Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/174292024-11-29T19:53:23Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Salmón, Marina author Álvarez-Díaz, Ruth author Fustero-Torre, Coral author Brehey, Oksana author Lechuga, Carmen G author Sanclemente, Manuel author Fernández-García, Fernando author López-García, Alejandra author Rodriguez Perales, Sandra author Martín-Guijarro, María Carmen author Bousquet-Mur, Emily author Morales-Cacho, Lucía author Mulero, Francisca author Al-Shahrour, Fatima author Martinez Garcia, Maria Dolores author Domínguez, Orlando author Caleiras, Eduardo author Ortega Jimenez, Sagrario author Guerra, Carmen author Musteanu, Monica author Drosten, Matthias author Barbacid, Mariano author 2023-04-03 KRASG12C inhibitors have revolutionized the clinical management of patients with KRASG12C-mutant lung adenocarcinoma. However, patient exposure to these inhibitors leads to the rapid onset of resistance. In this study, we have used genetically engineered mice to compare the therapeutic efficacy and the emergence of tumor resistance between genetic ablation of mutant Kras expression and pharmacological inhibition of oncogenic KRAS activity. Whereas Kras ablation induces massive tumor regression and prevents the appearance of resistant cells in vivo, treatment of KrasG12C/Trp53-driven lung adenocarcinomas with sotorasib, a selective KRASG12C inhibitor, caused a limited antitumor response similar to that observed in the clinic, including the rapid onset of resistance. Unlike in human tumors, we did not observe mutations in components of the RAS-signaling pathways. Instead, sotorasib-resistant tumors displayed amplification of the mutant Kras allele and activation of xenobiotic metabolism pathways, suggesting that reduction of the on-target activity of KRASG12C inhibitors is the main mechanism responsible for the onset of resistance. In sum, our results suggest that resistance to KRAS inhibitors could be prevented by achieving a more robust inhibition of KRAS signaling mimicking the results obtained upon Kras ablation. J Clin Invest . 2023;133(7):e164413. 10.1172/JCI164413 1558-8238 The Journal of clinical investigation 36928090 http://hdl.handle.net/20.500.12105/17429 Kras oncogene ablation prevents resistance in advanced lung adenocarcinomas.