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La activación sistémica de NRF2 contribuye a la eficacia terapéutica de los fármacos anticancerígenos KRAS-G12C
Liam Baird1,2,3, Lin Zhang4,5, Takanori Hidaka4,6
1Department of Biochemistry and Molecular Biology, Tohoku University, Tohoku Medical Megabank Organization, Sendai, Japan. liambaird@med.tohoku.ac.jp.
British journal of cancer
|September 1, 2025
Resumen
Los inhibidores de KRASG12C, Sotorasib y Adagrasib, activan inesperadamente NRF2, una proteína típicamente relacionada con la resistencia a los medicamentos. Esta inducción de NRF2 mejora la inmunidad contra el cáncer y contribuye a la
Área de la Ciencia:
- En el campo de la oncología
- Biología molecular
- Inmunología
Sus antecedentes:
- Las mutaciones oncogénicas de KRAS, en particular KRASG12C, son factores clave en varios tipos de cáncer, que históricamente plantean desafíos terapéuticos significativos.
- Las co-mutaciones en la vía KEAP1-NRF2 son comunes en los cánceres de pulmón con mutación KRAS, y la activación de NRF2 es un mecanismo conocido de resistencia a las terapias anticancerígenas.
Objetivo del estudio:
- Investigar el impacto de la activación aberrante de NRF2 en la respuesta clínica a los inhibidores de KRASG12C.
- Para aclarar el vínculo mecánico entre los inhibidores de KRASG12C y la modulación de NRF2.
Principales métodos:
- Utilizó knockouts genéticos para estudiar las alteraciones de la vía NRF2.
- Se empleó secuenciación de ARN de una sola célula (scRNA-seq) para analizar las respuestas celulares.
- Resonancia plasmónica de superficie aplicada (SPR) para determinar las interacciones con el fármaco objetivo.
Principales resultados:
- Se encontró que los inhibidores clínicamente aprobados de KRASG12C, Sotorasib y Adagrasib, inducían NRF2 en concentraciones fisiológicamente relevantes.
- La naturaleza electrofílica de estos fármacos les permite inhibir KRAS y unirse a los sensores de cisteína KEAP1, aumentando la expresión génica dependiente de NRF2.
Conclusiones:
- Los inhibidores de KRASG12C representan una nueva clase de agentes anticancerígenos que regulan positivamente el NRF2, una proteína a menudo asociada con la oncogénesis y la resistencia a los medicamentos.
- La activación de NRF2 por estos inhibidores mejora la inmunidad contra el cáncer tanto en las células tumorales como en las inmunitarias, contribuyendo a la eficacia clínica.
- Esta inducción global de NRF2 tiene implicaciones clínicas significativas para las terapias combinadas y la selección de pacientes en ensayos clínicos en curso.
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