학술논문
Mechanisms of Resistance to EGFR Inhibition Reveal Metabolic Vulnerabilities in Human GBM
Document Type
article
Author
McKinney, Andrew; Lindberg, Olle R; Engler, Jane R; Chen, Katharine Y; Kumar, Anupam; Gong, Henry; Lu, Kan V; Simonds, Erin F; Cloughesy, Timothy F; Liau, Linda M; Prados, Michael; Bollen, Andrew W; Berger, Mitchel S; Shieh, Joseph TC; James, C David; Nicolaides, Theodore P; Yong, William H; Lai, Albert; Hegi, Monika E; Weiss, William A; Phillips, Joanna J
Source
Molecular Cancer Therapeutics. 18(9)
Subject
Language
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.