Artikel
Candidate genes for sensitivity and resistance of human glioblastoma multiforme cell lines to erlotinib
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Autoren
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M.-E. Halatsch
- Neurochirurgische Klinik und Poliklinik, Universitätsklinikum Heidelberg
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S. Löw
- Neurochirurgische Klinik und Poliklinik, Universitätsklinikum Heidelberg
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K. Mursch
- Zentralklinik Bad Berka, Neurochirurgische Klinik, Bad Berka
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B. Orakcioglu
- Neurochirurgische Klinik und Poliklinik, Universitätsklinikum Heidelberg
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V. Vougioukas
- Albert-Ludwigs-Universität, Abteilung Allgemeine Neurochirurgie, Freiburg
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A. Unterberg
- Neurochirurgische Klinik und Poliklinik, Universitätsklinikum Heidelberg
| Veröffentlicht: | 20. Mai 2009 |
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Gliederung
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Objective: Erlotinib, an EGFR tyrosine kinase inhibitor, exerts widely variable antiproliferative effects on human GBM cell lines in vitro and in vivo. As those effects are independent of EGFR baseline expression levels, more complex genetic properties may form the molecular basis of the erlotinib-sensitive and erlotinib-resistant GBM phenotypes. The aim of the current study was to determine candidate genes mediating cellular response of human GBM towards erlotinib.
Methods: Complementary RNAs from cell lines selected to represent the sensitive, intermediately responsive and resistant phenotypes, respectively, were hybridized to CodeLink Human Whole Genome Bioarrays.
Results: Expression analysis of prospectively selected 814 genes involved in major proliferation and apoptosis signaling pathways identified 19 genes the expression of which significantly correlated with phenotype. Functional annotation analysis revealed two (DUSP4, STAT1) and ten (CACNG4, FGFR4, HSPA1B, HSPB1, NFATC1, NTRK1, RAC1, SMO, TCF7L1, TGFB3) genes conclusively associated with sensitivity and resistance to erlotinib, respectively. Moreover, five genes (BDNF, CARD6, FOSL1, HSPA9B, MYC) involved in antiapoptotic pathways were unexpectedly found to be associated with sensitivity.
Conclusions: By analyzing gene expressions in cell lines with sensitive, intermediately responsive and resistant phenotypes, this study proposes candidate genes for GBM response to erlotinib. The ten gene candidates for conferring GBM resistance to erlotinib potentially represent worthwhile therapeutic targets, interfering with which may enhance the efficacy of erlotinib against GBM. Five additional genes warrant further investigation regarding their roles as putative co-targets of erlotinib.
