The role of epidermal growth factor receptor in chordoma pathogenesis: A potential therapeutic target

Asem Shalaby, Nadège Presneau, Hongtao Ye, Dina Halai, Fitim Berisha, Bernadine Idowu, Andreas Leithner, Bernadette Liegl, Timothy R W Briggs, Krisztian Bacsi, Lars Gunnar Kindblom, Nicholas Athanasou, Maria Fernanda Amary, Pancras C W Hogendoorn, Roberto Tirabosco, Adrienne M. Flanagan

Research output: Contribution to journalArticle

71 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)336-346
Number of pages11
JournalJournal of Pathology
Volume223
Issue number3
DOIs
Publication statusPublished - Feb 2011

Keywords

  • Amplification
  • Chordoma
  • EGFR
  • Genetics
  • Polysomy
  • PTEN

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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  • Cite this

    Shalaby, A., Presneau, N., Ye, H., Halai, D., Berisha, F., Idowu, B., Leithner, A., Liegl, B., Briggs, T. R. W., Bacsi, K., Kindblom, L. G., Athanasou, N., Amary, M. F., Hogendoorn, P. C. W., Tirabosco, R., & Flanagan, A. M. (2011). The role of epidermal growth factor receptor in chordoma pathogenesis: A potential therapeutic target. Journal of Pathology, 223(3), 336-346. https://doi.org/10.1002/path.2818