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El p53 oncogénico induce errores mitóticos en las células de cáncer de pulmón mediante la copia de las bifurcaciones

Swati Palit Deb¹, Shilpa Singh², Lilia Gheghiani¹

¹Virginia Commonwealth University.

Research square

|August 20, 2025

Resumen

Las mutaciones oncogénicas de p53 causan estrés de replicación, lo que lleva a errores de ADN y crecimiento tumoral. Dirigirse a estos errores con inhibidores de ATM ofrece una nueva estrategia terapéutica para pacientes con cáncer de pulmón con mutaciones p53.

Área de la Ciencia:

En el campo de la oncología
Biología molecular
La genética

Sus antecedentes:

Las mutaciones oncogénicas de p53 (Onc-p53) son comunes en el pulmón y otros tumores sólidos, a menudo relacionados con aberraciones cromosómicas.
Los mecanismos por los cuales Onc-p53 impulsa la inestabilidad cromosómica y su papel en la progresión tumoral no se comprenden completamente.

Objetivo del estudio:

Para aclarar el mecanismo que vincula Onc-p53 a las aberraciones cromosómicas y el crecimiento tumoral.
Identificar posibles vulnerabilidades terapéuticas asociadas con la tumorigénesis impulsada por Onc-p53.

Principales métodos:

Se investigó el estrés de replicación y la dinámica de la bifurcación de la replicación del ADN en células con Onc-p53.
Se utilizó la video microscopía de lapso de tiempo para observar las aberraciones mitóticas y los errores de segregación de ADN.
Se emplearon modelos de tumores de pulmón xenograft con knockdown de horquillas de replicación activas y inhibidores de activación de ATM.

Principales resultados:

Onc-p53 induce el estrés de replicación, causando la re-copia de la bifurcación de la replicación del ADN y las posteriores aberraciones mitóticas y errores de segregación del ADN.
Estos errores activan la señalización ATM, estabilizando Onc-p53 y creando un ciclo de avance que acelera la formación de tumores.
La replicación dirigida y la activación de ATM indujeron sinérgicamente la apoptosis en células de cáncer de pulmón con Onc-p53, lo que demuestra un potencial terapéutico.

Conclusiones:

Un nuevo mecanismo conecta el estrés de replicación de Onc-p53 con su estabilización e inestabilidad cromosómica, acelerando el crecimiento del cáncer de pulmón.
Los errores mitóticos inducidos por Onc-p53 representan una vulnerabilidad dirigible para el desarrollo de terapias específicas para el tumor.
Estos hallazgos ofrecen una vía prometedora para el tratamiento de una proporción significativa de pacientes con cáncer con mutaciones p53.

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