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La resistencia al inhibidor BET surge de las células madre de la leucemia

Chun Yew Fong^1,2,3, Omer Gilan^1,2, Enid Y N Lam¹

¹Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.

|September 15, 2015

Resumen

Los inhibidores de la bromodomaína y de la proteína extra terminal (BET) son prometedores para la leucemia mieloide aguda. La resistencia surge de las células madre de la leucemia, en parte debido al aumento de la señalización de Wnt/β-catenina, que puede ser dirigida para restaurar la sensibilidad a los medicamentos.

Área de la Ciencia:

En el campo de la oncología
Biología molecular
Farmacología

Sus antecedentes:

Los inhibidores de la bromodomaína y de la proteína extra terminal (BET) son nuevas terapias dirigidas para el cáncer.
Los ensayos clínicos son prometedores para los inhibidores de BET, especialmente en la leucemia mieloide aguda (LMA).
La comprensión de los mecanismos de resistencia es fundamental para optimizar la eficacia del inhibidor BET.

Objetivo del estudio:

Investigar los mecanismos de resistencia al inhibidor I-BET en células madre hematopoyéticas y células progenitoras de ratón.
Identificar estrategias para superar la resistencia al inhibidor BET en la leucemia.

Principales métodos:

Clones unicelulares resistentes a I-BET generados a partir de células madre y progenitoras hematopoyéticas de ratón inmortalizadas por MLL-AF9.
Se ha evaluado la resistencia cruzada a otros inhibidores de la BET y la eliminación genética.
Los niveles de BRD4 ligados a la cromatina analizados y la expresión génica clave (por ejemplo, Myc).
Investigó el papel de la señalización de Wnt/β-catenina en la resistencia.

Principales resultados:

La resistencia a I-BET confirió resistencia cruzada a otros inhibidores de BET y knockdown genético.
La resistencia surgió de las células madre de la leucemia y no se debió al eflujo de fármacos o al metabolismo.
Se observó una reducción global de BRD4 ligado a la cromatina, con expresión de Myc inalterada.
El aumento de la señalización de Wnt/β-catenina fue identificado como un mecanismo clave de resistencia tanto en células leucémicas de ratón como humanas.

Conclusiones:

La resistencia a los inhibidores de BET en la LMA está mediada en parte por una mayor señalización de Wnt/β-catenina.
La señalización dirigida a Wnt/β-catenina puede restaurar la sensibilidad a los inhibidores de BET.
Estos hallazgos ofrecen información sobre la biología de la LMA y sugieren estrategias para mejorar el tratamiento con inhibidores de BET.

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