title: Candidate genes for sensitivity and resistance of human glioblastoma multiforme cell lines to erlotinib. Laboratory investigation.
abstract: OBJECTIVE
  The authors have previously reported that erlotinib, an EGFR tyrosine kinase inhibitor, exerts widely variable antiproliferative effects on 9 human glioblastoma multiforme (GBM) cell lines in vitro and in vivo. These effects were independent of EGFR baseline expression levels, raising the possibility that more complex genetic properties form the molecular basis of the erlotinib-sensitive and erlotinib-resistant GBM phenotypes. The aim of the present study was to determine candidate genes for mediating the cellular response of human GBMs to erlotinib.
  
  
  METHODS
  Complementary RNA obtained in cell lines selected to represent the sensitive, somewhat responsive, and resistant phenotypes were hybridized to CodeLink Human Whole Genome Bioarrays.
  
  
  RESULTS
  Expression analysis of 814 prospectively selected genes involved in major proliferation and apoptosis signaling pathways identified 19 genes whose expression significantly correlated with phenotype. Functional annotation analysis revealed that 2 genes (DUSP4 and STAT1) were significantly associated with sensitivity to erlotinib, and 10 genes (CACNG4, FGFR4, HSPA1B, HSPB1, NFATC1, NTRK1, RAC1, SMO, TCF7L1, and TGFB3) were associated with resistance to erlotinib. Moreover, 5 genes (BDNF, CARD6, FOSL1, HSPA9B, and MYC) involved in antiapoptotic pathways were unexpectedly found to be associated with sensitivity. Gene expressions were confirmed by quantitative polymerase chain reaction.
  
  
  CONCLUSIONS
  Based on an analysis of gene expressions in cell lines with sensitive, somewhat responsive, and resistant phenotypes, the authors propose candidate genes for GBM response to erlotinib. The 10 gene candidates for conferring GBM resistance to erlotinib may represent therapeutic targets for enhancing the efficacy of erlotinib against GBMs. Five additional genes warrant further investigation into their role as putative cotargets of erlotinib.
authors.affiliation: Neurochirurgische Klinik und Poliklinik, Ruprecht-Karls-Universität, Heidelberg, Germany. halatsch@aol.com
authors.forename: Marc-Eric
authors.initials: ME
authors.lastname: Halatsch
authors.forename: Sarah
authors.initials: S
authors.lastname: Löw
authors.forename: Kay
authors.initials: K
authors.lastname: Mursch
authors.forename: Thomas
authors.initials: T
authors.lastname: Hielscher
authors.forename: Ursula
authors.initials: U
authors.lastname: Schmidt
authors.forename: Andreas
authors.initials: A
authors.lastname: Unterberg
authors.forename: Vassilios I
authors.initials: VI
authors.lastname: Vougioukas
authors.forename: Friedrich
authors.initials: F
authors.lastname: Feuerhake
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D015870:Gene Expression; D055106:Genome-Wide Association Study; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride