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Open Access Publications from the University of California

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

  • Author(s): 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 YS
  • Damoiseaux, Robert
  • France, Bryan
  • Orozco, Nicholas
  • Visnyei, Koppany
  • Crisman, Thomas J
  • Gao, Fuying
  • Torres, Jorge Z
  • Coppola, Giovanni
  • Burlingame, Alma L
  • Kornblum, Harley I
  • et al.

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.

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