title: Frequent activation of EGFR in advanced chordomas.
abstract: BACKGROUND
  Chordomas are rare neoplasms, arising from notochordal remnants in the midline skeletal axis, for which the current treatment is limited to surgery and radiotherapy.  Recent reports suggest that receptor tyrosine kinases (RTK) might be essential for the survival or proliferation of chordoma cells, providing a rationale for RTK targeted therapy.  Nevertheless, the reported data are conflicting, most likely due to the assorted tumor specimens used for the studies and the heterogeneous methodological approaches.  In the present study, we performed a comprehensive characterization of this rare entity using a wide range of assays in search for relevant therapeutic targets.
  
  
  METHODS
  Histopathological features of 42 chordoma specimens, 21 primary and 21 advanced, were assessed by immunohistochemistry and fluorescent in situ hybridization (FISH) using PDGFRB, CSF1R, and EGFR probes.  Twenty-two of these cases, for which frozen material was available (nine primary and 13 advanced tumors), were selectively analyzed using the whole-genome 4.3K TK-CGH-array, phospho-kinase antibody array or Western immunoblotting.  The study was supplemented by direct sequencing of KIT, PDGFRB, CSF1R and EGFR.
  
  
  RESULTS
  We demonstrated that EGFR is frequently and the most significantly activated RTK in chordomas.  Furthermore, concurrent to EGFR activation, the tumors commonly reveal co-activation of alternative RTK.  The consistent activation of AKT, the frequent loss of the tumor suppressor PTEN allele, the recurrent activation of upstream RTK and of downstream effectors like p70S6K and mTOR, all indicate the PI3K/AKT pathway as an important mediator of transformation in chordomas.
  
  
  CONCLUSIONS
  Given the complexity of the signaling in chordomas, combined treatment regimens targeting multiple RTK and downstream effectors are likely to be the most effective in these tumors.  Personalized therapy with careful selection of the patients, based on the molecular profile of the specific tumor, is anticipated.
authors.forename: Barbara
authors.initials: B
authors.lastname: Dewaele
authors.forename: Francesca
authors.initials: F
authors.lastname: Maggiani
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Floris
authors.forename: Michele
authors.initials: M
authors.lastname: Ampe
authors.forename: Vanessa
authors.initials: V
authors.lastname: Vanspauwen
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wozniak
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot