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Mutaciones oncogénicas de la kinasa ALK en el neuroblastoma
Yuyan Chen1, Junko Takita, Young Lim Choi
1Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
Nature
|October 17, 2008
Resumen
Las alteraciones de la cinasa del linfoma anaplásico (ALK) son comunes en el neuroblastoma avanzado. Dirigirse a la ALK mutada puede ofrecer nuevas estrategias terapéuticas para este cáncer pediátrico intratable.
Área de la Ciencia:
- Oncología Oncología.
- Biología Molecular Biología Molecular
- Genética La genética.
Sus antecedentes:
- El neuroblastoma en estadio avanzado es un cáncer pediátrico desafiante con objetivos terapéuticos limitados.
- Las alteraciones genéticas conocidas incluyen la amplificación de MYCN y las pérdidas / ganancias cromosómicas.
- El desarrollo de tratamientos efectivos se ve obstaculizado por la escasez de objetivos moleculares confiables.
Objetivo del estudio:
- Para investigar el papel de la kinasa del linfoma anaplásico (ALK) como un objetivo terapéutico potencial en el neuroblastoma avanzado.
- Identificar alteraciones genéticas, incluidos cambios en el número de copias y mutaciones, dentro del gen ALK en muestras de neuroblastoma.
Principales métodos:
- Escaneos de todo el genoma utilizando microarrays de genotipado de polimorfismo de un solo nucleótido de alta densidad en 215 muestras de neuroblastoma primario.
- Secuenciación de ADN del gen ALK en tumores primarios y líneas celulares derivadas de neuroblastoma.
- Estudios funcionales que incluyen ensayos de actividad de kinasa, transformación de fibroblastos NIH3T3 y regulación a la baja de ALK mediada por interferencia de ARN.
Principales resultados:
- El locus ALK fue identificado como un objetivo recurrente de ganancia de número de copias y amplificación en el neuroblastoma avanzado.
- Se encontraron ocho nuevas mutaciones de sentido erróneo en el dominio de la ALK quinasa en el 6,1% de los tumores primarios (etapas 3-4) y en el 33% de las líneas celulares.
- Las kinasas ALK mutadas exhibieron un aumento de la autofosforilación y la actividad de la kinasa, transformando las células NIH3T3 y formando tumores en ratones.
- La regulación a la baja de la ALK suprimió la proliferación en células de neuroblastoma con ALK mutado.
Conclusiones:
- La kinasa del linfoma anaplásico (ALK) se altera con frecuencia en el neuroblastoma avanzado, lo que sugiere su participación en la patogénesis de la enfermedad.
- Las mutaciones en ALK confieren actividad oncogénica y representan posibles objetivos terapéuticos.
- Los inhibidores de la quinasa específicos de ALK son prometedores para mejorar los resultados clínicos en pacientes con neuroblastoma con alteraciones de ALK.
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