1. Combination therapy with potent PI3K and MAPK inhibitors overcomes adaptive kinome resistance to single agents in preclinical models of glioblastoma.
- Author
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McNeill RS, Canoutas DA, Stuhlmiller TJ, Dhruv HD, Irvin DM, Bash RE, Angus SP, Herring LE, Simon JM, Skinner KR, Limas JC, Chen X, Schmid RS, Siegel MB, Van Swearingen AED, Hadler MJ, Sulman EP, Sarkaria JN, Anders CK, Graves LM, Berens ME, Johnson GL, and Miller CR
- Subjects
- Animals, Apoptosis drug effects, Brain Neoplasms metabolism, Brain Neoplasms pathology, Cell Proliferation drug effects, Drug Synergism, Glioblastoma metabolism, Glioblastoma pathology, Humans, Mice, Phosphorylation, Signal Transduction drug effects, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Brain Neoplasms drug therapy, Drug Resistance, Neoplasm, Glioblastoma drug therapy, Mitogen-Activated Protein Kinases antagonists & inhibitors, Phosphoinositide-3 Kinase Inhibitors, Protein Kinase Inhibitors pharmacology
- Abstract
Background: Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Prognosis remains poor despite multimodal therapy. Developing alternative treatments is essential. Drugs targeting kinases within the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) effectors of receptor tyrosine kinase (RTK) signaling represent promising candidates., Methods: We previously developed a non-germline genetically engineered mouse model of GBM in which PI3K and MAPK are activated via Pten deletion and KrasG12D in immortalized astrocytes. Using this model, we examined the influence of drug potency on target inhibition, alternate pathway activation, efficacy, and synergism of single agent and combination therapy with inhibitors of these 2 pathways. Efficacy was then examined in GBM patient-derived xenografts (PDX) in vitro and in vivo., Results: PI3K and mitogen-activated protein kinase kinase (MEK) inhibitor potency was directly associated with target inhibition, alternate RTK effector activation, and efficacy in mutant murine astrocytes in vitro. The kinomes of GBM PDX and tumor samples were heterogeneous, with a subset of the latter harboring MAPK hyperactivation. Dual PI3K/MEK inhibitor treatment overcame alternate effector activation, was synergistic in vitro, and was more effective than single agent therapy in subcutaneous murine allografts. However, efficacy in orthotopic allografts was minimal. This was likely due to dose-limiting toxicity and incomplete target inhibition., Conclusion: Drug potency influences PI3K/MEK inhibitor-induced target inhibition, adaptive kinome reprogramming, efficacy, and synergy. Our findings suggest that combination therapies with highly potent, brain-penetrant kinase inhibitors will be required to improve patient outcomes., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)
- Published
- 2017
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