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Restauración farmacológica de la hidrólisis de GTP mediante RAS mutante
Antonio Cuevas-Navarro1, Yasin Pourfarjam1, Feng Hu1
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nature
|October 30, 2024
Resumen
Los nuevos inhibidores del tricomplejo ofrecen una nueva estrategia terapéutica para los cánceres mutados por RAS mediante la restauración de la actividad de la GTPasa. Estos pegamentos moleculares reclutan la ciclofilina A (CYPA) para estimular la hidrólisis de GTP, inhibiendo la proliferación de las células cancerosas.
Área de la Ciencia:
- En el campo de la oncología
- Biología molecular
- Descubrimiento de drogas
Sus antecedentes:
- Los proto-oncogenes del RAS (KRAS, NRAS, HRAS) son frecuentemente mutados en aproximadamente 3,4 millones de pacientes con cáncer anualmente.
- Las mutaciones en el RAS alteran la actividad de la GTPasa, dando lugar a una señalización y proliferación celular incontroladas.
- Las estrategias terapéuticas anteriores dirigidas a los mutantes de RAS no han tenido éxito.
Objetivo del estudio:
- Investigar el potencial de los inhibidores del tricomplejo como un nuevo enfoque terapéutico para los cánceres con mutación del RAS.
- Para aclarar el doble mecanismo de acción de estos inhibidores.
Principales métodos:
- Utilizó inhibidores tricomplejos diseñados para reclutar ciclofilina A (CYPA) al estado activo de la RAS.
- Se ha investigado el efecto de estos inhibidores sobre la unión al efector RAS y la hidrólisis de GTP.
- Se analizó la modulación específica de la mutación de los residuos de RAS por complejos CYPA ligados al fármaco.
Principales resultados:
- Los inhibidores tricomplejos demostraron un doble mecanismo: inhibición de la unión al efector RAS y estimulación de la hidrólisis de GTP.
- Los complejos CYPA ligados al fármaco modulan los residuos del motivo del interruptor RAS II, facilitando la hidrólisis de GTP de una manera específica para la mutación.
- Los mutantes del RAS sensibles a la estimulación de la actividad de la GTPasa mostraron una mayor susceptibilidad al tratamiento.
Conclusiones:
- La estimulación farmacológica de la hidrólisis de GTP potencia los efectos terapéuticos de los inhibidores del tricomplejo para los mutantes específicos de la RAS.
- Este estudio establece una base para el desarrollo de terapias que inhiben el crecimiento del cáncer mediante el aumento de la actividad mutante de la RAS GTPasa.
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