1 Hit in 0.035 sec


Kelli Ennis, Xizhi Feng, Catherine Gallo, David Plas
2015 Neuro-Oncology  
PTEN-inactivation in glioblastoma (GBM) triggers the hyperactivation of protein kinases, including mTOR and its downstream target, the ribosomal protein S6 kinase 1 (S6K1). Previous studies have demonstrated the potential efficacy of mTOR inhibitors for GBM therapy. We explored S6K1 inhibitors for potential cytotoxic effects in PTEN-deficient GBM cells. All S6K1 inhibitors were effective in reducing the phosphorylation of S6K1 substrates. However, analysis of the phosphorylation of the
more » ... ion of the inhibitor-bound S6K1 revealed important differences: some S6K1 inhibitors induced the phosphorylation of inhibitor-bound kinase, while others had little evidence of this effect. Induced phosphorylation of the inhibitor-bound kinase has been termed inhibitor hijacking. Our analysis in GBM cells suggests that S6K1 inhibitor hijacking is correlated with induced proximity to the upstream kinase, mTORC1. Evidence of inhibitor hijacking was inversely correlated with cytotoxic activity. We propose selective development of S6K1 inhibitors that avoid the hijacking effect for counteracting oncogenic signals in PTEN-deficient glioblastoma.
doi:10.1093/neuonc/nov204.66 fatcat:55v2jsbd45gbvpmfbtta7tu4oq