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

Neuro Oncol
Publication Year: 
Dan R Laks
Juan A Oses-Prieto
Alvaro G Alvarado
Jonathan Nakashima
Shreya Chand
Daniel B Azzam
Ankur A Gholkar
Jantzen Sperry
Kirsten Ludwig
Michael C Condro
Serli Nazarian
Anjelica Cardenas
Michelle Y S Shih
Robert Damoiseaux
Bryan France
Nicholas Orozco
Koppany Visnyei
Thomas J Crisman
Fuying Gao
Jorge Z Torres
Giovanni Coppola
Alma L Burlingame
Harley I Kornblum
PubMed link: 
Public Summary: 
Clinical trials of therapies directed against a gene called mTOR in glioblastoma cancer have had disappointing results. Drug resistance of glioblastoma cancer cells to mTOR-targeted drugs has limited their usefulness. Our data show how the glioblastoma cancer cells become resistant to mTOR-targetd drugs in human glioblastoma cancer cell cultures and points us toward new therapeutic strategies.
Scientific 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 and in vivo demonstrated that microtubule-associated protein (MAP)1B, previously associated predominantly with neurons, is a downstream effector of GSK3B-mediated resistance. Furthermore, we provide evidence that chronic rapamycin induces microtubule stability in a MAP1B-dependent manner in GBM cells. Additional experiments explicate a signaling pathway wherein combinatorial extracellular signal-regulated kinase (ERK)/mTOR targeting abrogates inhibitory phosphorylation of GSK3B, leads to phosphorylation of MAP1B, and confers sensitization. Conclusions: These data portray a compensatory molecular signaling network that imparts resistance to chronic mTOR inhibition in primary, human GBM cell cultures and points toward new therapeutic strategies.