title: Characterization and response of newly developed high-grade glioma cultures to the tyrosine kinase inhibitors, erlotinib, gefitinib and imatinib.
abstract: High-grade gliomas (HGG), are the most common aggressive brain tumours in adults. Inhibitors targeting growth factor signalling pathways in glioma have shown a low clinical response rate. To accurately evaluate response to targeted therapies further in vitro studies are necessary. Growth factor pathway expression using epidermal growth factor receptor (EGFR), mutant EGFR (EGFRvIII), platelet derived growth factor receptor (PDGFR), C-Kit and C-Abl together with phosphatase and tensin homolog (PTEN) expression and downstream activation of AKT and phosphorylated ribosomal protein S6 (P70S6K) was analysed in 26 primary glioma cultures treated with the tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib and imatinib. Response to TKIs was assessed using 50% inhibitory concentrations (IC(50)). Response for each culture was compared with the EGFR/PDGFR immunocytochemical pathway profile using hierarchical cluster analysis (HCA) and principal component analysis (PCA). Erlotinib response was not strongly associated with high expression of the growth factor pathway components. PTEN expression did not correlate with response to any of the three TKIs. Increased EGFR expression was associated with gefitinib response; increased PDGFR-α expression was associated with imatinib response. The results of this in vitro study suggest gefitinib and imatinib may have therapeutic potential in HGG tumours with a corresponding growth factor receptor expression profile.
authors.affiliation: National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland. paula.kinsella@dcu.ie
authors.forename: Paula
authors.initials: P
authors.lastname: Kinsella
authors.forename: Rachel
authors.initials: R
authors.lastname: Howley
authors.forename: Padraig
authors.initials: P
authors.lastname: Doolan
authors.forename: Colin
authors.initials: C
authors.lastname: Clarke
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Madden
authors.forename: Martin
authors.initials: M
authors.lastname: Clynes
authors.forename: Michael
authors.initials: M
authors.lastname: Farrell
authors.forename: Verena
authors.initials: V
authors.lastname: Amberger-Murphy
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D001932:Brain Neoplasms / Q000401:mortality / Q000473:pathology*; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D015870:Gene Expression; D005910:Glioma / Q000473:pathology*; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; C410723:epidermal growth factor receptor VIII; D000068877:Imatinib Mesylate; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D016315:Proto-Oncogene Proteins c-abl; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000077156:Gefitinib