Merck

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

Molecular cancer therapeutics (2019-07-05)
Andrew McKinney, Olle R Lindberg, Jane R Engler, Katharine Y Chen, Anupam Kumar, Henry Gong, Kan V Lu, Erin F Simonds, Timothy F Cloughesy, Linda M Liau, Michael Prados, Andrew W Bollen, Mitchel S Berger, Joseph T C Shieh, C David James, Theodore P Nicolaides, William H Yong, Albert Lai, Monika E Hegi, William A Weiss, Joanna J Phillips
RESUMO

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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Sigma-Aldrich
Tyrphostin AG 1478, ≥98%
Sigma-Aldrich
4-Diethylaminobenzaldehyde, 99%
Sigma-Aldrich
Lapatinib