Activation of Multiple ERBB Family Receptors Mediates Glioblastoma Cancer Stem-like Cell Resistance to EGFR-Targeted Inhibition
Epidermal growth factor receptor (EGFR) signaling is strongly implicated in glioblastoma (GBM) tumorigenesis. However, molecular agents targeting EGFR have demonstrated minimal efficacy in clinical trials, suggesting the existence of GBM resistance mechanisms. GBM cells with stem-like properties (C...
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doaj-532e2b057b8e4ce59b1099ff33e191ea2020-11-24T20:55:05ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022012-05-0114542042810.1596/neo.12432Activation of Multiple ERBB Family Receptors Mediates Glioblastoma Cancer Stem-like Cell Resistance to EGFR-Targeted InhibitionPaul A. Clark0Mari Iida1Daniel M. Treisman2Haviryaji Kalluri3Sathyapriya Ezhilan4Michael Zorniak5Deric L. Wheeler6John S. Kuo7Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WIDepartment of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WIDepartment of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WIDepartment of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WIDepartment of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WIDepartment of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WIDepartment of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WIDepartment of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WI Epidermal growth factor receptor (EGFR) signaling is strongly implicated in glioblastoma (GBM) tumorigenesis. However, molecular agents targeting EGFR have demonstrated minimal efficacy in clinical trials, suggesting the existence of GBM resistance mechanisms. GBM cells with stem-like properties (CSCs) are highly efficient at tumor initiation and exhibit therapeutic resistance. In this study, GBMCSC lines showed sphere-forming and tumor initiation capacity after EGF withdrawal from cell culture media, compared with normal neural stem cells that rapidly perished after EGF withdrawal. Compensatory activation of related ERBB family receptors (ERBB2 and ERBB3) was observed in GBM CSCs deprived of EGFR signal (EGF deprivation or cetuximab inhibition), suggesting an intrinsic GBM resistance mechanism for EGFR-targeted therapy. Dual inhibition of EGFR and ERBB2 with lapatinib significantly reduced GBM proliferation in colony formation assays compared to cetuximab-mediated EGFR-specific inhibition. Phosphorylation of downstream ERBB signaling components (AKT, ERK1/2) and GBM CSC proliferation were inhibited by lapatinib. Collectively, these findings show that GBM therapeutic resistance to EGFR inhibitors may be explained by compensatory activation of EGFR-related family members (ERBB2, ERBB3) enabling GBM CSC proliferation, and therefore simultaneous blockade of multiple ERBB family members may be required for more efficacious GBM therapy. http://www.sciencedirect.com/science/article/pii/S1476558612800170 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Paul A. Clark Mari Iida Daniel M. Treisman Haviryaji Kalluri Sathyapriya Ezhilan Michael Zorniak Deric L. Wheeler John S. Kuo |
spellingShingle |
Paul A. Clark Mari Iida Daniel M. Treisman Haviryaji Kalluri Sathyapriya Ezhilan Michael Zorniak Deric L. Wheeler John S. Kuo Activation of Multiple ERBB Family Receptors Mediates Glioblastoma Cancer Stem-like Cell Resistance to EGFR-Targeted Inhibition Neoplasia: An International Journal for Oncology Research |
author_facet |
Paul A. Clark Mari Iida Daniel M. Treisman Haviryaji Kalluri Sathyapriya Ezhilan Michael Zorniak Deric L. Wheeler John S. Kuo |
author_sort |
Paul A. Clark |
title |
Activation of Multiple ERBB Family Receptors Mediates Glioblastoma Cancer Stem-like Cell Resistance to EGFR-Targeted Inhibition |
title_short |
Activation of Multiple ERBB Family Receptors Mediates Glioblastoma Cancer Stem-like Cell Resistance to EGFR-Targeted Inhibition |
title_full |
Activation of Multiple ERBB Family Receptors Mediates Glioblastoma Cancer Stem-like Cell Resistance to EGFR-Targeted Inhibition |
title_fullStr |
Activation of Multiple ERBB Family Receptors Mediates Glioblastoma Cancer Stem-like Cell Resistance to EGFR-Targeted Inhibition |
title_full_unstemmed |
Activation of Multiple ERBB Family Receptors Mediates Glioblastoma Cancer Stem-like Cell Resistance to EGFR-Targeted Inhibition |
title_sort |
activation of multiple erbb family receptors mediates glioblastoma cancer stem-like cell resistance to egfr-targeted inhibition |
publisher |
Elsevier |
series |
Neoplasia: An International Journal for Oncology Research |
issn |
1476-5586 1522-8002 |
publishDate |
2012-05-01 |
description |
Epidermal growth factor receptor (EGFR) signaling is strongly implicated in glioblastoma (GBM) tumorigenesis. However, molecular agents targeting EGFR have demonstrated minimal efficacy in clinical trials, suggesting the existence of GBM resistance mechanisms. GBM cells with stem-like properties (CSCs) are highly efficient at tumor initiation and exhibit therapeutic resistance. In this study, GBMCSC lines showed sphere-forming and tumor initiation capacity after EGF withdrawal from cell culture media, compared with normal neural stem cells that rapidly perished after EGF withdrawal. Compensatory activation of related ERBB family receptors (ERBB2 and ERBB3) was observed in GBM CSCs deprived of EGFR signal (EGF deprivation or cetuximab inhibition), suggesting an intrinsic GBM resistance mechanism for EGFR-targeted therapy. Dual inhibition of EGFR and ERBB2 with lapatinib significantly reduced GBM proliferation in colony formation assays compared to cetuximab-mediated EGFR-specific inhibition. Phosphorylation of downstream ERBB signaling components (AKT, ERK1/2) and GBM CSC proliferation were inhibited by lapatinib. Collectively, these findings show that GBM therapeutic resistance to EGFR inhibitors may be explained by compensatory activation of EGFR-related family members (ERBB2, ERBB3) enabling GBM CSC proliferation, and therefore simultaneous blockade of multiple ERBB family members may be required for more efficacious GBM therapy.
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url |
http://www.sciencedirect.com/science/article/pii/S1476558612800170 |
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