Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS-ERK signaling.
Cancer Discov
; 4(3): 334-47, 2014 Mar.
Article
em En
| MEDLINE
| ID: mdl-24436048
ABSTRACT
The effects of selective phosphoinositide 3-kinase (PI3K) and AKT inhibitors were compared in human tumor cell lines in which the pathway is dysregulated. Both caused inhibition of AKT, relief of feedback inhibition of receptor tyrosine kinases, and growth arrest. However, only the PI3K inhibitors caused rapid induction of cell death. In seeking a mechanism for this phenomenon, we found that PI3K inhibition, but not AKT inhibition, causes rapid inhibition of wild-type RAS and of RAF-MEK-ERK signaling. Inhibition of RAS-ERK signaling is transient, rebounding a few hours after drug addition, and is required for rapid induction of apoptosis. Combined MEK and AKT inhibition also promotes cell death, and in murine models of HER2(+) cancer, either pulsatile PI3K inhibition or combined MEK and AKT inhibition causes tumor regression. We conclude that PI3K is upstream of RAS and AKT and that pulsatile inhibition of both pathways is sufficient for effective antitumor activity.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sistema de Sinalização das MAP Quinases
/
Inibidores de Proteínas Quinases
/
Proteínas Proto-Oncogênicas c-akt
/
Inibidores de Fosfoinositídeo-3 Quinase
/
Neoplasias
Limite:
Humans
Idioma:
En
Revista:
Cancer Discov
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Alemanha