A molecular cascade modulates MAP1B and confers resistance to mTOR inhibition in human glioblastoma.

ABSTRACT:

Background

Clinical trials of therapies directed against nodes of the signaling axis of phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin (mTOR) in glioblastoma (GBM) have had disappointing results. Resistance to mTOR inhibitors limits their efficacy.

Methods

To determine mechanisms of resistance to chronic mTOR inhibition, we performed tandem screens on patient-derived GBM cultures.

Results

An unbiased phosphoproteomic screen quantified phosphorylation changes associated with chronic exposure to the mTOR inhibitor rapamycin, and our analysis implicated a role for glycogen synthase kinase (GSK)3B attenuation in mediating resistance that was confirmed by functional studies. A targeted short hairpin RNA screen and further functional studies both in vitro a

SUBMITTER: Laks DR 

PROVIDER: S-EPMC5961175 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature