title: 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: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
authors: Stefan
authors: S
authors: Klingler
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
authors: Baofeng
authors: B
authors: Guo
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Jun
authors: J
authors: Yao
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Haiyan
authors: H
authors: Yan
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
authors: Ling
authors: L
authors: Zhang
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
authors: Angelina V
authors: AV
authors: Vaseva
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
authors: Sida
authors: S
authors: Chen
authors: Department of Pathology and Cell Biology, Columbia University, New York, New York.
authors: Peter
authors: P
authors: Canoll
authors: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: James W
authors: JW
authors: Horner
authors: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Y Alan
authors: YA
authors: Wang
authors: Department of Pathology, Weill-Cornell Medical College, New York, New York.
authors: Ji-Hye
authors: JH
authors: Paik
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Haoqiang
authors: H
authors: Ying
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. hzheng@cshl.edu.
authors: Hongwu
authors: H
authors: Zheng
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000077547:Crizotinib; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D007093:Imidazoles; D011720:Pyrazoles; D011725:Pyridines; D011799:Quinazolines; D011804:Quinolines; D000077547:Crizotinib; D000069347:Erlotinib Hydrochloride; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D004318:Doxycycline; C531198:dactolisib; D000077156:Gefitinib