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Las eliminaciones de pasajeros generan vulnerabilidades terapéuticas en el cáncer
Florian L Muller1, Simona Colla, Elisa Aquilanti
1Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Nature
|August 17, 2012
Resumen
Las células cancerosas con genes de la enolasa 1 (ENO1) eliminados exhiben vulnerabilidades a las terapias dirigidas a ENO1. El silenciamiento del gen ENO2 relacionado inhibe selectivamente estas células cancerosas, revelando una potencial nueva estrategia de tratamiento.
Área de la Ciencia:
- Genómica del cáncer Genómica del cáncer.
- Oncología Molecular Oncología Molecular
- Descubrimiento de Drogas Descubrimiento de Drogas
Sus antecedentes:
- La inactivación del gen supresor tumoral a través de la deleción homocigótica es común en el cáncer.
- Estas deleciones pueden afectar a los genes vecinos (genes pasajeros).
- Las deleciones de genes pasajeros pueden crear vulnerabilidades terapéuticas si afectan a las familias de genes esenciales y redundantes.
Objetivo del estudio:
- Investigar el potencial terapéutico de las vulnerabilidades colaterales derivadas de las deleciones genéticas en el cáncer.
- Explorar el papel de la deleción del gen glicolítico enolasa 1 (ENO1) en el glioblastoma (GBM).
- Evaluar el impacto de la focalización en miembros de la familia de enolasa redundantes en GBM eliminados por ENO1.
Principales métodos:
- Se utilizó ARN de horquilla corta (shRNA) para silenciar la enolasa 2 (ENO2) en las células GBM.
- Se evaluaron los efectos del silenciamiento de ENO2 en el crecimiento celular de GBM, la supervivencia y el potencial tumorigénico.
- Evaluó la toxicidad selectiva del inhibidor de la enolasa fosfonoacetohidroxamato en células GBM ENO1-borradas versus células GBM ENO1-intactas y astrocitos normales.
Principales resultados:
- El silenciamiento mediado por ARN de la horquilla de pelo corto de ENO2 inhibió selectivamente el crecimiento, la supervivencia y el potencial tumorigénico de las células GBM eliminadas de ENO1.
- El inhibidor de la enolasa fosfonoacetohidroxamato demostró toxicidad selectiva hacia las células GBM eliminadas ENO1.
- Las células GBM con eliminación de ENO1 toleraban la pérdida de ENO1 debido a la expresión de ENO2.
Conclusiones:
- La eliminación homocigótica de ENO1 en GBM crea una vulnerabilidad colateral que puede explotarse apuntando a ENO2.2.
- Los inhibidores de enolasa muestran toxicidad selectiva contra las células GBM con deleciones ENO1.
- El principio de vulnerabilidad colateral ofrece una estrategia terapéutica prometedora para los cánceres con deleciones de genes pasajeros.
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