Epidermal Growth Factor Receptor Extracellular Domain Mutations in Glioblastoma Present Opportunities for Clinical Imaging and Therapeutic Development

Zev A Binder; Amy Haseley Thorne; Spyridon Bakas; E Paul Wileyto; Michel Bilello; Hamed Akbari; Saima Rathore; Sung Min Ha; Logan Zhang; Cole J Ferguson; Sonika Dahiya; Wenya Linda Bi; David A Reardon; Ahmed Idbaih; Joerg Felsberg; Bettina Hentschel; Michael Weller; Stephen J Bagley; Jennifer J D Morrissette; MacLean P Nasrallah; Jianhui Ma; Ciro Zanca; Andrew M Scott; Laura Orellana; Christos Davatzikos; Frank B Furnari; Donald M O'Rourke

doi:10.1016/j.ccell.2018.06.006

Epidermal Growth Factor Receptor Extracellular Domain Mutations in Glioblastoma Present Opportunities for Clinical Imaging and Therapeutic Development

Cancer Cell. 2018 Jul 9;34(1):163-177.e7. doi: 10.1016/j.ccell.2018.06.006.

Authors

Zev A Binder¹, Amy Haseley Thorne², Spyridon Bakas³, E Paul Wileyto⁴, Michel Bilello³, Hamed Akbari³, Saima Rathore³, Sung Min Ha³, Logan Zhang⁵, Cole J Ferguson⁶, Sonika Dahiya⁶, Wenya Linda Bi⁷, David A Reardon⁸, Ahmed Idbaih⁹, Joerg Felsberg¹⁰, Bettina Hentschel¹¹, Michael Weller¹², Stephen J Bagley¹³, Jennifer J D Morrissette¹⁴, MacLean P Nasrallah¹⁵, Jianhui Ma², Ciro Zanca², Andrew M Scott¹⁶, Laura Orellana¹⁷, Christos Davatzikos³, Frank B Furnari¹⁸, Donald M O'Rourke¹⁹

Affiliations

¹ Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Biomedical Image Computing and Analytics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
² Ludwig Institute for Cancer Research, La Jolla, San Diego 92093, USA.
³ Center for Biomedical Image Computing and Analytics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁴ Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶ Division of Neuropathology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63108, USA.
⁷ Center for Skull Base and Pituitary Surgery, Department of Neurosurgery, Brigham and Woman's Hospital, Harvard Medical Center, Boston, MA 02115, USA.
⁸ Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁹ Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, Paris 75013, France.
¹⁰ Institute of Neuropathology, Heinrich Heine University, Medical Faculty, Moorenstrasse 5, Duesseldorf 40225, Germany.
¹¹ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Medical Faculty, Härtelstrasse 16, Leipzig 04107, Germany.
¹² Department of Neurology, University Hospital and University of Zurich, Zurich 8091, Switzerland.
¹³ Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁴ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁵ Division of Neuropathology, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁶ Olivia Newton-John Cancer Research Institute, La Trobe University, Melbourne, Australia.
¹⁷ Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden; Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
¹⁸ Ludwig Institute for Cancer Research, La Jolla, San Diego 92093, USA. Electronic address: ffurnari@ucsd.edu.
¹⁹ Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Biomedical Image Computing and Analytics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: donald.orourke@uphs.upenn.edu.

Abstract

We explored the clinical and pathological impact of epidermal growth factor receptor (EGFR) extracellular domain missense mutations. Retrospective assessment of 260 de novo glioblastoma patients revealed a significant reduction in overall survival of patients having tumors with EGFR mutations at alanine 289 (EGFR^A289D/T/V). Quantitative multi-parametric magnetic resonance imaging analyses indicated increased tumor invasion for EGFR^A289D/T/V mutants, corroborated in mice bearing intracranial tumors expressing EGFR^A289V and dependent on ERK-mediated expression of matrix metalloproteinase-1. EGFR^A289V tumor growth was attenuated with an antibody against a cryptic epitope, based on in silico simulation. The findings of this study indicate a highly invasive phenotype associated with the EGFR^A289V mutation in glioblastoma, postulating EGFR^A289V as a molecular marker for responsiveness to therapy with EGFR-targeting antibodies.

Keywords: A289D/T/V; EGFR; EGFR oncogenes; EGFR targeted therapy; GBM; glioblastoma; glioma; radiogenomics; radiomics; survival.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Animals
Antibodies, Monoclonal / pharmacology*
Antineoplastic Agents, Immunological / pharmacology*
Brain Neoplasms / diagnostic imaging
Brain Neoplasms / genetics*
Brain Neoplasms / metabolism
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Child
Child, Preschool
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / genetics*
ErbB Receptors / immunology
ErbB Receptors / metabolism
Extracellular Signal-Regulated MAP Kinases / metabolism
Female
Genetic Predisposition to Disease
Glioblastoma / diagnostic imaging
Glioblastoma / genetics*
Glioblastoma / metabolism
Humans
Image Interpretation, Computer-Assisted
Infant
Infant, Newborn
Machine Learning
Magnetic Resonance Imaging*
Male
Matrix Metalloproteinase 1 / metabolism
Mice, Nude
Middle Aged
Mutation, Missense*
Neoplasm Invasiveness
Phenotype
Phosphorylation
Predictive Value of Tests
Protein Domains
Retrospective Studies
Signal Transduction / drug effects
Xenograft Model Antitumor Assays
Young Adult

Substances

Antibodies, Monoclonal
Antineoplastic Agents, Immunological
epidermal growth factor receptor VIII
monoclonal antibody 806
EGFR protein, human
ErbB Receptors
Extracellular Signal-Regulated MAP Kinases
MMP1 protein, human
Matrix Metalloproteinase 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding