1657P - Hypoxia regulation of sensitivity to the mechanistic target of rapamycin kinase inhibition (mTORki) in glioblastoma multiforme

Date 28 September 2014
Event ESMO 2014
Session Poster Display session
Topics Central Nervous System Malignancies
Translational Research
Presenter Beatrice Gini
Citation Annals of Oncology (2014) 25 (suppl_4): iv564-iv573. 10.1093/annonc/mdu359
Authors B. Gini1, B. Bonetti1, P. Mischel2
  • 1Neurological And Movement Sciences, University of Verona, 37134 - Verona/IT
  • 2Pathology, LICR-UCSD, 92093 - La Jolla/US

Abstract

Aim

Hypoxia is a marker of advanced cancer progression frequently correlated with treatment refractory tumors. The role that hypoxia exerts in determining cancer treatment resistance has not been clarified yet. In the present study we evaluated the hypoxia dependency of mTORki resistance in glioblastoma multiforme (GBM).

Methods

We performed in vivo tests aimed at developing an mTORki resistance model. We assessed an intra-tumoral hypoxia index, quantified as the ratio between total HIF-1-alpha and hydroxy-HIF-1-alpha. Then we recapitulated in vitro the mTORki resistance growing GBM cells in hypoxia.

Results

The molecular signature associated with mTORki resistance in GBM reveals the emergence of a putative nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB)-dependent reactivation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) pathway. Further, the onset of the resistance phenotype was hypoxia-inducible factor-1-alpha (HIF-1-alpha) independent.

Conclusions

These data provide for the first time the evidence that hypoxia induced mTORki resistance potentially relies on an NF-kB-mediated reactivation of the PI3K/PKB signaling. Additional pre-clinical studies will be needed to confirm the clinical implications of our insights.

Disclosure

P. Mischel: In 2011 and early 2012, Dr. Mischel engaged in a research contract with Celgene and received an honorarium to attend their advisory board meeting. Since then, Dr. Mischel has had no further financial interactions with Celgene. All other authors have declared no conflicts of interest.