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Potencial generalizado de resistencia impulsada por el factor de crecimiento a los inhibidores de la quinasa
Timothy R Wilson1, Jane Fridlyand, Yibing Yan
1Research Oncology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
Nature
|July 6, 2012
Resumen
Las células cancerosas pueden desarrollar resistencia a los medicamentos mediante la activación de vías alternativas de supervivencia. La orientación de las receptoras tirosina quinasas (RTK) con ligandos específicos, como el HGF para el melanoma resistente al inhibidor de BRAF, puede superar esta resistencia.
Área de la Ciencia:
- Oncología Oncología.
- Biología Molecular Biología Molecular
- Farmacología Farmacología.
Sus antecedentes:
- Los inhibidores de la quinasa son objetivos clínicamente validados de fármacos contra el cáncer.
- La resistencia a los medicamentos, tanto innata como adquirida, limita la eficacia de los inhibidores de la quinasa.
- La resistencia a menudo implica la activación de señales redundantes de supervivencia celular, particularmente a través de las receptoras tirosina quinasas (RTK).
Objetivo del estudio:
- Investigar el papel de la señalización redundante del receptor tirosina quinasa (RTK) en la concesión de resistencia a los inhibidores de la quinasa.
- Identificar ligandos específicos de RTK que pueden superar la resistencia a los fármacos en las líneas celulares de cáncer.
- Explorar las implicaciones clínicas de los mecanismos de resistencia mediados por RTK.
Principales métodos:
- Utilizó un panel de líneas de células cancerosas humanas adictas a la quinasa.
- Las células cancerosas expuestas a varios ligandos de RTK para evaluar el rescate de la sensibilidad a los medicamentos.
- Se investigó el efecto del factor de crecimiento hepatocitario (HGF) en las células de melanoma mutantes de BRAF tratadas con el inhibidor de BRAF PLX4032 (vemurafenib).
Principales resultados:
- La mayoría de las líneas celulares de cáncer probadas podrían ser rescatadas de la sensibilidad al inhibidor de la kinasa por la exposición a los ligandos de RTK.
- El factor de crecimiento hepatocitario (HGF) confirió resistencia al inhibidor de BRAF PLX4032 (vemurafenib) en las células de melanoma mutantes de BRAF.
- Se ha demostrado una extensa redundancia en las vías de señalización transducidas por RTK dentro de las células cancerosas.
Conclusiones:
- Los ligandos de la receptor tirosina quinasa (RTK) juegan un papel importante en la resistencia innata y adquirida a los medicamentos contra el cáncer dirigidos a la quinasa.
- La redundancia de las vías de señalización de RTK presenta un gran desafío para lograr respuestas duraderas a los inhibidores de la quinasa.
- Las estrategias dirigidas a la señalización de RTK pueden ser cruciales para superar la resistencia a los medicamentos en varios tipos de cáncer.
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