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Pequeñas moléculas co-direccionadas a CKIα y las cinasas transcripcionales CDK7/9 controlan la LMA en modelos preclínicos

  • 0The Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Cell +

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28 de agosto de 2018

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28 de agosto de 2018

Ver abstracta en PubMed

Resumen

Este resumen es generado por máquina.

Los nuevos inhibidores dirigidos a la caseína quinasa I alfa (CKIα), CDK7 y CDK9 activan la p53 y suprimen la leucemia al dirigirse a los super potenciadores. Estos agentes son prometedores para curar la leucemia mieloide aguda (LMA) mientras se preserva el desarrollo normal de las células sanguíneas.

Área De La Ciencia

  • En el campo de la oncología
  • Biología molecular
  • Desarrollo de drogas

Sus Antecedentes

  • La ablación de la caseína quinasa I alfa (CKIα) activa la p53, y su degradación es clave para la eficacia de la lenalidomida en la preleucemia.
  • La leucemia mieloide aguda (LMA) es impulsada por oncogenes regulados por super potenciadores (SE).

Objetivo Del Estudio

  • Desarrollar nuevos inhibidores dirigidos a CKIα, CDK7 y CDK9 para una mayor actividad antileucémica.
  • Investigar el mecanismo de acción de estos inhibidores sobre las SE y la activación de p53 en la LMA.

Principales Métodos

  • Desarrollo de inhibidores duales dirigidos a las CKIα y las cinasas transcripcionales CDK7/9.
  • Análisis de SE en células primarias de LMA de ratón y xenografts derivados de pacientes.
  • Evaluación de la estabilización de p53, la supresión de la transcripción génica y la inducción de la apoptosis.
  • Evaluación de la eficacia terapéutica en modelos de LMA en ratones y trasplantes xenográficos.

Principales Resultados

  • Los inhibidores desarrollados co-dirigen a CKIα, CDK7 y CDK9, aumentando la activación de p53.
  • Los inhibidores eliminan las SE recién adquiridas en las células de LMA y suprimen la transcripción oncogénica impulsada por SE.
  • La inhibición combinada estabiliza sinérgicamente la p53, induce la apoptosis y elimina selectivamente los progenitores de la leucemia.
  • Eficacia terapéutica demostrada en múltiples modelos de LMA, incluidos el MLL-AF9 y los xenografts derivados de pacientes.

Conclusiones

  • La doble inhibición de CKIα/CDK7/9 representa una estrategia terapéutica prometedora para la LMA.
  • Los inhibidores se dirigen selectivamente a las células leucémicas al interrumpir la adicción oncogénica impulsada por SE.
  • Este enfoque ofrece potencial para la curación de la leucemia con la preservación de la hematopoyesis.

Palabras clave:

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