Mechanisms of Resistance to EGFR Inhibition Reveal Metabolic Vulnerabilities in Human GBM.

Details

Serval ID
serval:BIB_B63D76C24EA8
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Mechanisms of Resistance to EGFR Inhibition Reveal Metabolic Vulnerabilities in Human GBM.
Journal
Molecular cancer therapeutics
Author(s)
McKinney A., Lindberg O.R., Engler J.R., Chen K.Y., Kumar A., Gong H., Lu K.V., Simonds E.F., Cloughesy T.F., Liau L.M., Prados M., Bollen A.W., Berger M.S., Shieh JTC, James C.D., Nicolaides T.P., Yong W.H., Lai A., Hegi M.E., Weiss W.A., Phillips J.J.
ISSN
1538-8514 (Electronic)
ISSN-L
1535-7163
Publication state
Published
Issued date
09/2019
Peer-reviewed
Oui
Volume
18
Number
9
Pages
1565-1576
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Amplification of the epidermal growth factor receptor gene (EGFR) represents one of the most commonly observed genetic lesions in glioblastoma (GBM); however, therapies targeting this signaling pathway have failed clinically. Here, using human tumors, primary patient-derived xenografts (PDX), and a murine model for GBM, we demonstrate that EGFR inhibition leads to increased invasion of tumor cells. Further, EGFR inhibitor-treated GBM demonstrates altered oxidative stress, with increased lipid peroxidation, and generation of toxic lipid peroxidation products. A tumor cell subpopulation with elevated aldehyde dehydrogenase (ALDH) levels was determined to comprise a significant proportion of the invasive cells observed in EGFR inhibitor-treated GBM. Our analysis of the ALDH1A1 protein in newly diagnosed GBM revealed detectable ALDH1A1 expression in 69% (35/51) of the cases, but in relatively low percentages of tumor cells. Analysis of paired human GBM before and after EGFR inhibitor therapy showed an increase in ALDH1A1 expression in EGFR-amplified tumors (P < 0.05, n = 13 tumor pairs), and in murine GBM ALDH1A1-high clones were more resistant to EGFR inhibition than ALDH1A1-low clones. Our data identify ALDH levels as a biomarker of GBM cells with high invasive potential, altered oxidative stress, and resistance to EGFR inhibition, and reveal a therapeutic target whose inhibition should limit GBM invasion.
Keywords
Aldehyde Dehydrogenase 1/metabolism, Animals, Brain Neoplasms/drug therapy, Brain Neoplasms/metabolism, Brain Neoplasms/pathology, Cell Line, Tumor, Cell Proliferation/drug effects, Dasatinib/pharmacology, Drug Resistance, Neoplasm/drug effects, ErbB Receptors/antagonists & inhibitors, ErbB Receptors/metabolism, Erlotinib Hydrochloride/pharmacology, Glioblastoma/drug therapy, Glioblastoma/metabolism, Glioblastoma/pathology, Humans, Mice, Oxidative Stress/drug effects, Protein Kinase Inhibitors/pharmacology, Retinal Dehydrogenase/metabolism, Xenograft Model Antitumor Assays/methods
Pubmed
Web of science
Create date
08/07/2019 12:50
Last modification date
07/07/2020 5:20
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