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Los tumores con mutantes BRAF de clase 3 son sensibles a la inhibición de las RAS activadas

Zhan Yao¹, Rona Yaeger², Vanessa S Rodrik-Outmezguine¹

¹Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.

|August 8, 2017

Resumen

Los investigadores identificaron una tercera clase de mutantes de BRAF (clase 3) que son dependientes de RAS y mejoran la señalización de ERK. Estos mutantes BRAF requieren mecanismos de activación de RAS coexistentes, lo que tiene un impacto en las estrategias de tratamiento del cáncer.

Área de la Ciencia:

En el campo de la oncología
Biología molecular
Genética del cáncer

Sus antecedentes:

Las mutaciones BRAF son comunes en los tumores humanos, con más de 200 alelos identificados.
Las mutaciones conocidas de BRAF (clase 1 y 2) activan vías de señalización independientes del RAS.
La comprensión de las subclases mutantes de BRAF es crucial para las terapias dirigidas al cáncer.

Objetivo del estudio:

Caracterizar una clase de mutantes de BRAF recién identificados (clase 3) con actividad de quinasas alterada.
Para aclarar los mecanismos de señalización y la dependencia de RAS de los mutantes BRAF de Clase 3.
Para determinar las implicaciones terapéuticas de las distintas clases de mutantes BRAF.

Principales métodos:

Caracterización funcional de los mutantes del BRAF.
Análisis de la unión RAS-GTP y la activación de CRAF.
Investigación de la modulación de la vía de señalización ERK.
Correlación de la clase de mutantes BRAF con las alteraciones genéticas coexistentes en los tumores.

Principales resultados:

Los mutantes BRAF de clase 3 presentan una actividad de quinasas alterada y son dependientes del RAS.
Estos mutantes se unen más fuertemente a RAS-GTP y mejoran la activación de CRAF, lo que lleva a una mayor señalización de ERK.
Las mutaciones BRAF de clase 3 en el melanoma están asociadas con mutaciones RAS o deleciones de NF1.
En los cánceres de pulmón y colorrectal, los mutantes BRAF de Clase 3 están relacionados con la activación de la RAS mediada por la tirosina quinasa del receptor.

Conclusiones:

Se han definido tres clases funcionales distintas de mutantes BRAF basadas en sus mecanismos de señalización.
La dependencia de RAS y las vías de activación de ERK de los mutantes BRAF de clase 3 influyen en su respuesta a las terapias dirigidas.
La orientación de las vías de activación de RAS es una estrategia terapéutica potencial para los tumores con mutaciones BRAF de Clase 3.

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