title: Glioblastoma-derived epidermal growth factor receptor carboxyl-terminal deletion mutants are transforming and are sensitive to EGFR-directed therapies.
abstract: Genomic alterations of the epidermal growth factor receptor (EGFR) gene play a crucial role in pathogenesis of glioblastoma multiforme (GBM). By systematic analysis of GBM genomic data, we have identified and characterized a novel exon 27 deletion mutation occurring within the EGFR carboxyl-terminus domain (CTD), in addition to identifying additional examples of previously reported deletion mutations in this region. We show that the GBM-derived EGFR CTD deletion mutants are able to induce cellular transformation in vitro and in vivo in the absence of ligand and receptor autophosphorylation. Treatment with the EGFR-targeted monoclonal antibody, cetuximab, or the small molecule EGFR inhibitor, erlotinib, effectively impaired tumorigenicity of oncogenic EGFR CTD deletion mutants. Cetuximab in particular prolonged the survival of intracranially xenografted mice with oncogenic EGFR CTD deletion mutants, compared with untreated control mice. Therefore, we propose that erlotinib and, especially, cetuximab treatment may be a promising therapeutic strategy in GBM patients harboring EGFR CTD deletion mutants.
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors: Jeonghee
authors: J
authors: Cho
authors: Sandra
authors: S
authors: Pastorino
authors: Qing
authors: Q
authors: Zeng
authors: Xiaoyin
authors: X
authors: Xu
authors: William
authors: W
authors: Johnson
authors: Scott
authors: S
authors: Vandenberg
authors: Roel
authors: R
authors: Verhaak
authors: Andrew D
authors: AD
authors: Cherniack
authors: Hideo
authors: H
authors: Watanabe
authors: Amit
authors: A
authors: Dutt
authors: Jihyun
authors: J
authors: Kwon
authors: Ying S
authors: YS
authors: Chao
authors: Robert C
authors: RC
authors: Onofrio
authors: Derek
authors: D
authors: Chiang
authors: Yuki
authors: Y
authors: Yuza
authors: Santosh
authors: S
authors: Kesari
authors: Matthew
authors: M
authors: Meyerson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D000068818:Cetuximab; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005091:Exons / Q000235:genetics; D017353:Gene Deletion; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D041681:NIH 3T3 Cells; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000068818:Cetuximab