TitleA molecular cascade modulates MAP1B and confers resistance to mTOR inhibition in human glioblastoma.
Publication TypeJournal Article
Year of Publication2018
AuthorsLaks DR, Oses-Prieto JA, Alvarado AG, Nakashima J, Chand S, Azzam DB, Gholkar AA, Sperry J, Ludwig K, Condro MC, Nazarian S, Cardenas A, Shih MYS, Damoiseaux R, France B, Orozco N, Visnyei K, Crisman TJ, Gao F, Torres JZ, Coppola G, Burlingame AL, Kornblum HI
JournalNeuro Oncol
Volume20
Issue6
Pagination764-775
Date Published2018 May 18
ISSN1523-5866
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.

DOI10.1093/neuonc/nox215
Alternate JournalNeuro-oncology
PubMed ID29136244
PubMed Central IDPMC5961175
Grant ListP30 NS062691 / NS / NINDS NIH HHS / United States
P50 CA211015 / CA / NCI NIH HHS / United States
R01 NS052563 / NS / NINDS NIH HHS / United States