AXL as a modulator of sunitinib response in glioblastoma cell lines.
Exp Cell Res
; 332(1): 1-10, 2015 Mar 01.
Article
em En
| MEDLINE
| ID: mdl-25637219
Receptor tyrosine kinase (RTK) targeted therapy has been explored for glioblastoma treatment. However, it is unclear which RTK inhibitors are the most effective and there are no predictive biomarkers available. We recently identified the RTK AXL as a putative target for the pan-RTK inhibitors cediranib and sunitinib, which are under clinical trials for glioblastoma patients. Here, we provide evidence that AXL activity can modulate sunitinib response in glioblastoma cell lines. We found that AXL knockdown conferred lower sensitivity to sunitinib by rescuing migratory defects and inhibiting apoptosis in cells expressing high AXL basal levels. Accordingly, overactivation of AXL by its ligand GAS6 rendered AXL positive glioblastoma cells more sensitive to sunitinib. AXL knockdown induced a cellular rewiring of several growth signaling pathways through activation of RTKs, such as EGFR, as well as intracellular pathways such as MAPK and AKT. The combination of sunitinib with a specific AKT inhibitor reverted the resistance of AXL-silenced cells to sunitinib. Together, our results suggest that sunitinib inhibits AXL and AXL activation status modulates therapy response of glioblastoma cells to sunitinib. Moreover, it indicates that combining sunitinib therapy with AKT pathway inhibitors could overcome sunitinib resistance.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirróis
/
Proteínas Proto-Oncogênicas
/
Receptores Proteína Tirosina Quinases
/
Inibidores da Angiogênese
/
Indóis
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Exp Cell Res
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Brasil
País de publicação:
Estados Unidos