1. Combined CDK4/6 and mTOR Inhibition Is Synergistic against Glioblastoma via Multiple Mechanisms
- Author
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Breanna Brenneman, Roger Abounader, Inan Olmez, Ichiro Nakano, Norbert Leitinger, Agnieszka Bronisz, Benjamin Purow, Jakub Godlewski, Laryssa Manigat, Ying Zhang, Aizhen Xiao, Mouadh Benamar, Tarek Abbas, Jeongwu Lee, and Vlad Serbulea
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Cancer Research ,Pyridines ,Antineoplastic Agents ,Apoptosis ,Pharmacology ,Palbociclib ,Models, Biological ,Piperazines ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Everolimus ,Protein Kinase Inhibitors ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Caspase 7 ,biology ,Cell growth ,Cyclin-dependent kinase 4 ,Caspase 3 ,TOR Serine-Threonine Kinases ,RPTOR ,Cyclin-Dependent Kinase 4 ,Drug Synergism ,Cell Cycle Checkpoints ,Cyclin-Dependent Kinase 6 ,Xenograft Model Antitumor Assays ,Disease Models, Animal ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Disease Progression ,Female ,Cyclin-dependent kinase 6 ,Glioblastoma ,medicine.drug ,Signal Transduction - 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. Clin Cancer Res; 23(22); 6958–68. ©2017 AACR.
- Published
- 2017