A molecular cascade modulates MAP1B and confers resistance to mTOR inhibition in human glioblastoma. Issue 6 (9th November 2017)

• Record Type: Journal Article
• Authors: Laks, Dan R; Oses-Prieto, Juan A; Alvarado, Alvaro G; Nakashima, Jonathan; Chand, Shreya; Azzam, Daniel B; Gholkar, Ankur A; Sperry, Jantzen; Ludwig, Kirsten; Condro, Michael C; Nazarian, Serli; Cardenas, Anjelica; Shih, Michelle Y S; Damoiseaux, Robert; France, Bryan; Orozco, Nicholas; Visnyei, Koppany; Crisman, Thomas J; Gao, Fuying; Torres, Jorge Z; Coppola, Giovanni; Burlingame, Alma L; Kornblum, Harley I
• Is Part Of: Neuro-oncology. Volume 20:Issue 6(2018)
• Page Start: 764
• Page End: 775
• Publication Date: 2017-11-09
• Subjects: cancer -- ERK -- glioma -- glioblastoma -- GSK3B -- MAP1B -- MEK -- microtubule -- mTOR -- tubulin; Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/nox215
• Languages: English
• ISSNs: 1522-8517

Abstract

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.