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Las mutaciones silenciosas revelan vulnerabilidad terapéutica en los cánceres de RAS Q61
Yoshihisa Kobayashi1,2,3, Chhayheng Chhoeu4, Jiaqi Li5
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. yoshikob@ncc.go.jp.
Nature
|March 3, 2022
Resumen
Los investigadores descubrieron que una mutación silenciosa de KRAS (G60G) es esencial para la producción funcional de oncogenes KRAS (Q61K) en el cáncer. Este hallazgo revela una nueva estrategia terapéutica dirigida a los cánceres RAS (Q61) mediante la interferencia con el empalme.
Área de la Ciencia:
- En el campo de la oncología
- Biología molecular
- La genética
Sus antecedentes:
- Las proteínas de la familia RAS son oncogenes clave en los cánceres humanos, y los inhibidores de KRAS ((G12C) muestran eficacia clínica.
- Las terapias existentes no se dirigen a las variantes NRAS, HRAS o KRAS que no sean G12C, lo que deja una necesidad significativa no satisfecha.
- El estado funcional de las proteínas RAS está intrincadamente relacionado con modificaciones post-transcripcionales como el splicing alternativo.
Objetivo del estudio:
- Para aclarar el mecanismo por el cual se produce una variante funcional KRAS ((Q61K).
- Identificar nuevas dianas terapéuticas para los cánceres impulsados por mutaciones RAS ((Q61).
- Explorar el papel de las mutaciones silenciosas en la activación oncogénica y la posible intervención terapéutica.
Principales métodos:
- Investigó el papel de la mutación silenciosa KRAS G60G en la producción de proteínas KRAS ((Q61K) utilizando técnicas de biología molecular.
- Se analizaron los eventos de empalme alternativos y la terminación prematura de la proteína asociada con las mutaciones KRAS.
- Oligonucleótidos antisenso específicos de mutantes diseñados y probados dirigidos a motivos de potenciador de empalme exónico (ESE) para inhibir el empalme aberrante.
Principales resultados:
- Se requiere una mutación silenciosa de KRAS G60G para la producción de KRAS funcional (Q61K) al evitar la formación de sitios de empalme crípticos y empalme alternativo.
- KRAS ((Q61K) y la mutación silenciosa G60G/A59A se encontraron concordantes en tres cohortes independientes de cáncer de páncreas.
- Los oligonucleótidos antisentido dirigidos a los motivos ESE inhibieron selectivamente la función RAS ((Q61), demostrando efectos terapéuticos in vitro e in vivo.
Conclusiones:
- El estudio descubre un nuevo mecanismo dependiente del empalme para la activación del oncogén RAS ((Q61K).
- Esta investigación identifica una estrategia terapéutica selectiva de mutantes para los cánceres de RAS (Q61) al dirigirse al empalme aberrante.
- Los hallazgos sugieren que la explotación de las vulnerabilidades del empalme podría ser un enfoque prometedor para el tratamiento de otros cánceres genéticos.
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