Journal
NEOPLASIA
Volume 14, Issue 5, Pages 420-+Publisher
ELSEVIER SCIENCE INC
DOI: 10.1596/neo.12432
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Funding
- National Institutes of Health (NIH) [NIH 5T32AG027566, NIH T32GM007507]
- UW Carbone Cancer Center [NIH P30 CA014529]
- HEADRUSH Brain Tumor Research Professorship
- AANS-NREF Young Clinician Investigator Award
- Loff Memorial Fund
- Department of Neurological Surgery, Graduate School, and Medical School at the University of Wisconsin
- National Cancer Institute [P30CA014520]
- National Center for Research Resources [1UL1RR025011]
- NIH
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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, GBM CSC 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. Neoplasia (2012) 14, 420-428
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