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Un mutante inactivo de la Braf quinasa induce el adenocarcinoma pulmonar
Patricia Nieto1, Chiara Ambrogio1, Laura Esteban-Burgos1
1Experimental Oncology, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain.
Nature
|August 8, 2017
Resumen
Las mutaciones BRAF inactivantes inician el adenocarcinoma pulmonar al alterar la señalización de MAPK. El BRAF de tipo salvaje es crucial para el crecimiento del tumor, y su pérdida puede provocar lesiones letales.
Área de la Ciencia:
- En el campo de la oncología
- Biología molecular
- Genética del cáncer
Sus antecedentes:
- El evento oncogénico inicial en los adenocarcinomas pulmonares es a menudo desconocido, lo que dificulta el desarrollo de terapias dirigidas.
- Las mutaciones BRAF inactivadoras son frecuentes en los tumores pulmonares, a diferencia de las mutaciones activadoras comunes en otros cánceres.
Objetivo del estudio:
- Investigar el papel de las mutaciones inactivadoras de BRAF como eventos iniciadores en la oncogénesis pulmonar.
- Explorar la interacción entre la señalización BRAF, KRAS y MAPK en el desarrollo y la progresión del adenocarcinoma pulmonar.
Principales métodos:
- Modelos de ratón in vivo que expresan mutaciones Braf ((D631A) y Kras ((G12V) inactivas en la quinasa.
- Análisis del inicio del tumor, la progresión y la diferenciación del tipo de célula.
- Inhibición farmacológica de MEK (Mek) para modular la señalización de MAPK.
Principales resultados:
- La expresión de la quinasa inactiva Braf ((D631A) desencadena el adenocarcinoma pulmonar en ratones.
- La coexpresión de Kras ((G12V) y Braf ((D631A) acelera la iniciación y progresión del tumor a través de la cinasa Craf.
- La ablación de Braf de tipo salvaje conduce a un aumento de la señalización de MAPK y la toxicidad oncogénica, pero también induce la transdiferenciación de las células del clavo y lesiones letales.
Conclusiones:
- Las mutaciones inactivadoras de BRAF están iniciando eventos en el cáncer de pulmón.
- La intensidad de la señal de la vía MAPK determina críticamente el fenotipo del tumor y la célula de origen.
- La orientación de BRAF y la comprensión de la dinámica de la vía MAPK son cruciales para el tratamiento del adenocarcinoma pulmonar.
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