Development of resistance to EGFR targeted therapy in malignant glioma can occur through EGFR dependent and independent mechanisms

Klingler, S., Guo, B., Yao, J., Yan, H., Zhang, L., Vaseva, A. V., Chen, S., Canoll, P., Horner, J. W., Wang, Y. A., Paik, J. H., Ying, H., Zheng, H. (May 2015) Development of resistance to EGFR targeted therapy in malignant glioma can occur through EGFR dependent and independent mechanisms. Cancer Research, 75 (10). pp. 2109-2119. ISSN 0008-5472

URL: http://www.ncbi.nlm.nih.gov/pubmed/25808866
DOI: 10.1158/0008-5472.can-14-3122

Abstract

Epidermal growth factor receptor (EGFR) is highly amplified, mutated and overexpressed in human malignant gliomas. Despite its prevalence and growth-promoting functions, therapeutic strategies to inhibit EGFR kinase activity have not been translated into profound beneficial effects in glioma clinical trials. To determine the roles of oncogenic EGFR signaling in gliomagenesis and tumor maintenance, we generated a novel glioma mouse model driven by inducible expression of a mutant EGFR (EGFR*). Using combined genetic and pharmacological interventions, we revealed that EGFR*-driven gliomas were insensitive to EGFR tyrosine kinase inhibitors although they could efficiently inhibit EGFR* auto-phosphorylation in vitro and in vivo. This is in contrast to genetic suppression of EGFR* induction which led to significant tumor regression and prolonged animal survival. But in spite of their initial response to genetic EGFR* extinction, all tumors would relapse and propagate independent of EGFR*. We further showed that EGFR*-independent tumor cells existed prior to treatment and were responsible for relapse following genetic EGFR* suppression. And addition of PI3K/mTOR inhibitor could significantly delay relapse and prolong animal survival. Our studies together reveal important mechanistic insights into tumor therapeutic resistance development and provide a platform for testing therapies targeting aberrant EGFR signaling-driven malignant gliomas.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > EGFR
diseases & disorders > cancer > cancer types > glioblastoma
CSHL Authors:
Communities: CSHL labs > Zheng lab
CSHL Cancer Center Program > Signal Transduction
Depositing User: Matt Covey
Date: May 2015
Date Deposited: 27 Mar 2015 20:15
Last Modified: 16 Oct 2015 14:07
PMCID: PMC4433602
Related URLs:
URI: http://repository.cshl.edu/id/eprint/31296

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