Kras oncogene ablation prevents resistance in advanced lung adenocarcinomas.

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...

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Detalles Bibliográficos
Autores: Salmón, Marina, Álvarez-Díaz, Ruth, Fustero-Torre, Coral, Brehey, Oksana, Lechuga, Carmen G, Sanclemente, Manuel, Fernández-García, Fernando, López-García, Alejandra, Rodriguez Perales, Sandra, Martín-Guijarro, María Carmen, Bousquet-Mur, Emily, Morales-Cacho, Lucía, Mulero, Francisca, Al-Shahrour, Fatima, Martinez Garcia, Maria Dolores, Domínguez, Orlando, Caleiras, Eduardo, Ortega Jimenez, Sagrario, Guerra, Carmen, Musteanu, Monica, Drosten, Matthias, Barbacid, Mariano
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/17429
Acceso en línea:http://hdl.handle.net/20.500.12105/17429
Access Level:acceso abierto
Palabra clave:Adenocarcinoma of Lung
Lung Neoplasms
Animals
Mice
Mutation
Oncogenes
Proto-Oncogene Proteins p21(ras)
Signal Transduction
Descripción
Sumario: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.

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