Development of Resistance to EGFR-Targeted Therapy in Malignant Glioma Can Occur through EGFR-Dependent and -Independent Mechanisms.

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 pharmacologic interventions, we revealed that EGFR*-driven gliomas were insensitive to EGFR tyrosine kinase inhibitors, although they could efficiently inhibit EGFR* autophosphorylation in vitro and in vivo. This is in contrast with the genetic suppression of EGFR* induction that led to significant tumor regression and prolonged animal survival. However, despite 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, the addition of a PI3K/mTOR inhibitor could significantly delay relapse and prolong animal survival. Our findings shed mechanistic insight into EGFR drug resistance in glioma and provide a platform to test therapies targeting aberrant EGFR signaling in this setting.

• Authors: Stefan Klingler, Baofeng Guo, Jun Yao, Haiyan Yan, Ling Zhang, Angelina V Vaseva, Sida Chen, Peter Canoll, James W Horner, Y Alan Wang, Ji-Hye Paik, Haoqiang Ying, Hongwu Zheng
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 10 Pg. 2109-19 (May 15 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 25808866 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Cyclin-Dependent Kinase Inhibitor p16
• Imidazoles
• Pyrazoles
• Pyridines
• Quinazolines
• Quinolines
• Crizotinib
• Erlotinib Hydrochloride
• EGFR protein, mouse
• ErbB Receptors
• PTEN Phosphohydrolase
• Pten protein, mouse
• Doxycycline
• dactolisib
• Gefitinib

Topics

• Animals
• Brain Neoplasms (drug therapy, metabolism)
• Crizotinib
• Cyclin-Dependent Kinase Inhibitor p16 (genetics, metabolism)
• Doxycycline (pharmacology)
• Drug Resistance, Neoplasm
• ErbB Receptors (antagonists & inhibitors, genetics, metabolism)
• Erlotinib Hydrochloride
• Gefitinib
• Glioma (drug therapy, metabolism)
• Humans
• Imidazoles (pharmacology)
• Mice, Inbred C57BL
• Mice, Transgenic
• Molecular Targeted Therapy
• PTEN Phosphohydrolase (genetics, metabolism)
• Phosphorylation
• Protein Processing, Post-Translational
• Pyrazoles (pharmacology)
• Pyridines (pharmacology)
• Quinazolines (pharmacology)
• Quinolines (pharmacology)
• Tumor Cells, Cultured