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El inhibidor pan-KRAS desactiva la señalización oncogénica y el crecimiento tumoral

Dongsung Kim^1,2, Lorenz Herdeis³, Dorothea Rudolph³

¹Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

|May 31, 2023

Resumen

Los investigadores descubrieron un nuevo inhibidor no covalente que se dirige a la forma inactiva de las proteínas KRAS, incluidas las mutaciones comunes del cáncer. Este inhibidor pan-KRAS es prometedor para el tratamiento de varios cánceres impulsados por KRAS al bloquear el crecimiento tumoral sin dañar las células sanas.

Área de la Ciencia:

En el campo de la oncología
Biología molecular
Descubrimiento de drogas

Sus antecedentes:

Las mutaciones KRAS son frecuentes en muchos cánceres, impulsando el crecimiento del tumor.
Las terapias actuales se dirigen principalmente a la mutación KRAS G12C.
Apuntar a otros mutantes de KRAS y al tipo salvaje de KRAS sigue siendo un desafío.

Objetivo del estudio:

Descubrir y caracterizar un nuevo inhibidor no covalente dirigido al estado inactivo de KRAS.
Evaluar la selectividad del inhibidor para KRAS frente a NRAS y HRAS.
Evaluar el potencial terapéutico de este inhibidor pan-KRAS en modelos preclínicos.

Principales métodos:

En el cribado silico y en los ensayos bioquímicos para identificar y caracterizar el inhibidor.
Ensayos basados en células para evaluar la inhibición de la señalización y la proliferación de KRAS.
Estudios in vivo con modelos de ratón de cánceres con mutación KRAS.

Principales resultados:

Se identificó un inhibidor no covalente que se une a KRAS en su conformación inactiva con alta afinidad.
El inhibidor demostró selectividad para el KRAS, evitando el NRAS y el HRAS.
Bloqueó efectivamente el intercambio de nucleótidos, inhibiendo el KRAS de tipo salvaje y un amplio espectro de mutantes de KRAS.
La inhibición de la señalización descendente y la proliferación fue específica de las células cancerosas mutantes KRAS.
El crecimiento tumoral fue suprimido en ratones con cáncer mutante KRAS sin efectos adversos significativos.

Conclusiones:

La mayoría de las oncoproteínas KRAS dependen del intercambio de nucleótidos para la activación y el ciclo entre estados activos e inactivos.
Un nuevo inhibidor no covalente ofrece una estrategia terapéutica potencial para una amplia gama de cánceres impulsados por KRAS.
Los inhibidores pan-KRAS requieren una mayor investigación clínica para el tratamiento del cáncer.

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