Journal
MOLECULAR CANCER THERAPEUTICS
Volume 18, Issue 9, Pages 1565-1576Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-18-1330
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Funding
- NIH/NINDS [R01 NS081117]
- NIH/NCI [U01CA168878, U01 CA229345, P50CA221747, R01 CA179071, P50-CA211015, P50CA097257]
- Oncosuisse [OCS-01680-02-2005]
- T.J. Martell Foundation
- Gerson and Barbara Bakar Philanthropic Fund
- Sence Foundation
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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.
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