title: The role of epidermal growth factor receptor in chordoma pathogenesis: a potential therapeutic target.
abstract: Chordoma, the molecular hallmark of which is T (brachyury), is a rare malignant bone tumour with a high risk of local recurrence and a tumour from which metastatic disease is a common late event. Currently, there is no effective drug therapy for treating chordomas, although there is evidence that some patients respond to the empirical use of epidermal growth factor receptor (EGFR) antagonists. The aim of this study was to determine the role of EGFR in the pathogenesis of chordoma. Paraffin-embedded material from 173 chordomas from 160 patients [sacro-coccygeal (n = 94), skull-based (n = 50), and mobile spine (n = 16)] was analysed by immunohistochemistry and revealed total EGFR expression in 69% of cases analysed. Of 147 informative chordomas analysed by FISH, 38% revealed high-level EGFR polysomy, 4% high-level polysomy with focal amplification, 18% low-level polysomy, and 39% disomy. Phospho-receptor tyrosine kinase array membranes showed EGFR activation in the chordoma cell line U-CH1 and all of the three chordomas analysed. Direct sequencing of EGFR (exons 18-21), KRAS, NRAS, HRAS (exons 2, 3), and BRAF (exons 11, 15) using DNA from 62 chordomas failed to reveal mutations. PTEN expression was absent by immunohistochemistry in 19 of 147 (13%) analysed chordomas, only one of which revealed high-level polysomy of EGFR. The EGFR inhibitor tyrphostin (AG 1478) markedly inhibited proliferation of the chordoma cell line U-CH1 in vitro and diminished EGFR phosphorylation in a dose-dependant manner, a finding supported by inhibition of phosphorylated Erk1/2. p-Akt was suppressed to a much lesser degree in these experiments. There was no reduction of T as assessed by western blotting. These data implicate aberrant EGFR signalling in the pathogenesis of chordoma. This study provides a strategy for patient stratification for treatment with EGFR antagonists.
authors.affiliation: UCL Cancer Institute, 72 Huntley Street, London WC1 6BT, UK.
authors.forename: Asem
authors.initials: A
authors.lastname: Shalaby
authors.forename: Nadège
authors.initials: N
authors.lastname: Presneau
authors.forename: Hongtao
authors.initials: H
authors.lastname: Ye
authors.forename: Dina
authors.initials: D
authors.lastname: Halai
authors.forename: Fitim
authors.initials: F
authors.lastname: Berisha
authors.forename: Bernadine
authors.initials: B
authors.lastname: Idowu
authors.forename: Andreas
authors.initials: A
authors.lastname: Leithner
authors.forename: Bernadette
authors.initials: B
authors.lastname: Liegl
authors.forename: Timothy R W
authors.initials: TR
authors.lastname: Briggs
authors.forename: Krisztian
authors.initials: K
authors.lastname: Bacsi
authors.forename: Lars-Gunnar
authors.initials: LG
authors.lastname: Kindblom
authors.forename: Nicholas
authors.initials: N
authors.lastname: Athanasou
authors.forename: Maria Fernanda
authors.initials: MF
authors.lastname: Amary
authors.forename: Pancras C W
authors.initials: PC
authors.lastname: Hogendoorn
authors.forename: Roberto
authors.initials: R
authors.lastname: Tirabosco
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Flanagan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002817:Chordoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004252:DNA Mutational Analysis / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism; D011799:Quinazolines; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D019292:Skull Base Neoplasms / Q000378:metabolism; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D009363:Neoplasm Proteins; D011799:Quinazolines; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D020032:Tyrphostins; C101044:RTKI cpd; C508053:ERBB2 protein, human