Combined CDK4/6 and mTOR inhibition is synergistic against glioblastoma via multiple mechanisms

Inan Olmez, Breanna Brenneman, Aizhen Xiao, Vlad Serbulea, Mouadh Benamar, Ying Zhang, Laryssa Manigat, Tarek Abbas, Jeongwu Lee, Ichiro Nakano, Jakub Godlewski, Agnieszka Bronisz, Roger Abounader, Norbert Leitinger, Benjamin Purow

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Purpose: Glioblastoma (GBM) is a deadly brain tumor marked by dysregulated signaling and aberrant cell-cycle control. Molecular analyses have identified that the CDK4/6-Rb-E2F axis is dysregulated in about 80% of GBMs. Single-agent CDK4/6 inhibitors have failed to provide durable responses in GBM, suggesting a need to combine them with other agents. We investigate the efficacy of the combination of CDK4/6 inhibition and mTOR inhibition against GBM. Experimental Design: Preclinical in vitro and in vivo assays using primary GBM cell lines were performed. Results: We show that the CDK4/6 inhibitor palbociclib suppresses the activity of downstream mediators of the mTOR pathway, leading to rebound mTOR activation that can be blocked by the mTOR inhibitor everolimus. We further show that mTOR inhibition with everolimus leads to activation of the Ras mediator Erk that is reversible with palbociclib. The combined treatment strongly disrupts GBM metabolism, resulting in significant apoptosis. Further increasing the utility of the combination for brain cancers, everolimus significantly increases the brain concentration of palbociclib. Conclusions: Our findings demonstrate that the combination of CDK4/6 and mTOR inhibition has therapeutic potential against GBM and suggest it should be evaluated in a clinical trial.

Original languageEnglish (US)
Pages (from-to)6958-6968
Number of pages11
JournalClinical Cancer Research
Volume23
Issue number22
DOIs
StatePublished - Nov 15 2017

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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