Combined CDK4/6 and mTOR Inhibition Is Synergistic against Glioblastoma via Multiple Mechanisms

• Published in: Clinical cancer research 2017-11, Vol.23 (22), p.6958-6968
• Main Authors: Olmez, Inan, Brenneman, Breanna, Xiao, Aizhen, Serbulea, Vlad, Benamar, Mouadh, Zhang, Ying, Manigat, Laryssa, Abbas, Tarek, Lee, Jeongwu, Nakano, Ichiro, Godlewski, Jakub, Bronisz, Agnieszka, Abounader, Roger, Leitinger, Norbert, Purow, Benjamin
• Format: Article
• Language: English
• Subjects: Aberration; Activation; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Brain; Brain tumors; Cancer; Caspase 3 - metabolism; Caspase 7 - metabolism; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Combined treatment; Cyclin-dependent kinase 4; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Disease Models, Animal; Disease Progression; Drug Synergism; E2F protein; Everolimus - pharmacology; Experimental design; Female; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - metabolism; Glioblastoma - pathology; Humans; Inhibition; Inhibitors; Metabolism; Mice; Models, Biological; Piperazines - pharmacology; Protein Kinase Inhibitors - pharmacology; Pyridines - pharmacology; Signal Transduction - drug effects; Signaling; TOR protein; TOR Serine-Threonine Kinases - antagonists & inhibitors; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-17-0803

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. Preclinical and assays using primary GBM cell lines were performed. 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. 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. .