MEK Inhibition Suppresses Growth of Atypical Teratoid/Rhabdoid Tumors.

Abstract

Atypical teratoid/rhabdoid (AT/RT) tumors are the most common malignant brain tumor of infancy and have a poor prognosis. We have previously identified very high expression of LIN28A and/or LIN28B in AT/RT tumors and showed that AT/RT have corresponding increased expression of the mitogen-activated protein (MAP) kinase pathway. Binimetinib is a novel inhibitor of mitogen-activated protein kinase (MAP2K1 or MEK), and is currently in pediatric phase II clinical trials for low-grade glioma. We hypothesized that binimetinib would inhibit growth of AT/RT cells by suppressing the MAP kinase pathway. Binimetinib inhibited AT/RT growth at nanomolar concentrations. Binimetinib decreased cell proliferation and induced apoptosis in AT/RT cells and significantly reduced AT/RT tumor growth in flank xenografts. Our data suggest that MAP kinase pathway inhibition could offer a potential avenue for treating these highly aggressive tumors.

• Authors: Shubin Shahab, Jeffrey Rubens, Harpreet Kaur, Heather Sweeney, Charles G Eberhart, Eric H Raabe
• Journal: Journal of neuropathology and experimental neurology (J Neuropathol Exp Neurol) Vol. 79 Issue 7 Pg. 746-753 (07 01 2020) ISSN: 1554-6578 [Electronic] England
• PMID: 32472116 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 American Association of Neuropathologists, Inc. All rights reserved.

Chemical References

• Benzimidazoles
• binimetinib

Topics

• Animals
• Benzimidazoles (pharmacology, therapeutic use)
• Brain Neoplasms (drug therapy, enzymology, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects, physiology)
• Humans
• MAP Kinase Signaling System (drug effects, physiology)
• Mice
• Rhabdoid Tumor (drug therapy, enzymology, pathology)
• Teratoma (drug therapy, enzymology, pathology)
• Xenograft Model Antitumor Assays (methods)