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Un inhibidor de molécula pequeña diseñado de un ARN no codificante sensibiliza a los cánceres HER2 negativos a

Matthew G Costales¹, Dominic G Hoch¹, Daniel Abegg¹

¹Department of Chemistry , The Scripps Research Institute , 130 Scripps Way , Jupiter , Florida 33458 , United States.

Journal of the American Chemical Society

|February 7, 2019

Resumen

Una nueva molécula pequeña se dirige selectivamente a miR-515 para aumentar los niveles de esfingosina quinasa 1 (SK1) y esfingosina 1-fosfato (S1P), sensibilizando las células cancerosas HER2 a las terapias anti-HER2 como Herceptin.

Área de la Ciencia:

La bioquímica
Biología molecular
Investigación del cáncer

Sus antecedentes:

La desregulación del microARN (miRNA) está implicada en el cáncer.
Las alteraciones de las vías de la esfingosina quinasa 1 (SK1) y la esfingosina 1-fosfato (S1P) están relacionadas con la progresión del cáncer y la resistencia a los medicamentos.
Los cánceres HER2- negativos (HER2-) a menudo carecen de sensibilidad a las terapias dirigidas a HER2 como Herceptin.

Objetivo del estudio:

Para diseñar una pequeña molécula que selectivamente se dirige a un precursor de miRNA específico.
Investigar los efectos de esta molécula en la vía SK1/S1P y el fenotipo de las células cancerosas.
Determinar si esta molécula puede sensibilizar las células cancerosas HER2 a las terapias dirigidas existentes.

Principales métodos:

Diseño y síntesis de una molécula dimérica pequeña (2) dirigida al precursor de la horquilla miR-515.
Ensayos basados en células para evaluar los niveles de SK1 y S1P, la migración celular y la expresión de proteínas.
En el caso de los productos químicos, se recomienda que se utilicen los siguientes métodos:
Evaluación de la sensibilización a la terapia anti-HER2 (Herceptin) en varias líneas de células cancerosas.

Principales resultados:

La molécula pequeña (2) inhibió selectivamente la producción de miR-515, lo que condujo a un aumento de los niveles de SK1 y S1P y a una mayor migración celular.
El perfil del objetivo confirmó la unión selectiva del compuesto 2 al precursor de la horquilla miR-515.
Compuesto 2 que regula las proteínas asociadas al cáncer, incluyendo ERBB2/HER2, en las células MCF-7.
Aplicación del compuesto 2 sensibilizado al cáncer de mama HER2, el carcinoma hepatocelular y las células de cáncer de mama triple negativo a Herceptin.
Las células epiteliales normales del seno que carecen de expresión de miR-515 no fueron afectadas por el compuesto 2.

Conclusiones:

Una nueva molécula pequeña se dirige selectivamente a miR-515, modulando la vía SK1 / S1P.
Este enfoque sensibiliza eficazmente las células cancerosas HER2 a las terapias dirigidas a HER2, ofreciendo una potencial estrategia de medicina de precisión.
Los hallazgos sugieren un método para ampliar la utilidad terapéutica de los fármacos dirigidos contra el cáncer existentes para cánceres previamente insensibles.

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