Candidate genes for sensitivity and resistance of human glioblastoma multiforme cell lines to erlotinib. Laboratory investigation.
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.
Halatsch
Marc-Eric
ME
Neurochirurgische Klinik und Poliklinik, Ruprecht-Karls-Universität, Heidelberg, Germany. halatsch@aol.com
Löw
Sarah
S
Mursch
Kay
K
Hielscher
Thomas
T
Schmidt
Ursula
U
Unterberg
Andreas
A
Vougioukas
Vassilios I
VI
Feuerhake
Friedrich
F
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
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride