Halatsch Marce E, Löw Sarah, Hielscher Thomas, Schmidt Ursula, Unterberg Andreas, Vougioukas Vassilios I
Department of Neurosurgery, Ruprecht Karls University, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany.
Anticancer Res. 2008 Nov-Dec;28(6A):3725-8.
Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, exerts highly variable antiproliferative effects on human glioblastoma multiforme (GBM) cells in vitro and in vivo. As these effects are independent of EGFR baseline expression levels, more complex genetic signatures may form the molecular basis of the erlotinib-sensitive and erlotinib-resistant GBM phenotypes. The aim of the current study was to determine which genes within the EGFR signaling pathway are candidates for mediating the cellular response of human GBM towards erlotinib.
Complementary (c)RNAs from cell lines selected to represent the sensitive, intermediately responsive and resistant phenotypes, respectively, were hybridized to CodeLink Human Whole Genome Bioarrays.
Expression analysis of the prospectively selected 244 genes whose products constitute the EGFR signaling pathway identified five genes the expression of which significantly correlated with phenotype. Functional annotation analysis revealed one (STATI) and two (FKBP14, RAC1) genes conclusively associated with sensitivity and resistance to erlotinib, respectively. Moreover, two additional genes (PTGER4, MYC) were unexpectedly found to be associated with sensitivity. The gene expressions were confirmed by quantitative polymerase chain reaction.
Five genes within the EGFR signaling pathway may modulate GBM response to erlotinib, which further emphasizes the importance of this pathway for the biology of GBM.
厄洛替尼是一种表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，在体外和体内对多形性胶质母细胞瘤（GBM）细胞具有高度可变的抗增殖作用。由于这些作用与EGFR基线表达水平无关，更复杂的基因特征可能构成GBM对厄洛替尼敏感和耐药表型的分子基础。本研究的目的是确定EGFR信号通路中的哪些基因是介导人类GBM对厄洛替尼细胞反应的候选基因。
分别从代表敏感、中度反应和耐药表型的细胞系中提取互补（c）RNA，与CodeLink人类全基因组生物芯片进行杂交。
对预先选择的244个其产物构成EGFR信号通路的基因进行表达分析，确定了5个基因，其表达与表型显著相关。功能注释分析显示，一个基因（STATI）和两个基因（FKBP14、RAC1）分别与对厄洛替尼的敏感性和耐药性密切相关。此外，意外发现另外两个基因（PTGER4、MYC）与敏感性相关。通过定量聚合酶链反应证实了基因表达。
EGFR信号通路中的5个基因可能调节GBM对厄洛替尼的反应，这进一步强调了该通路对GBM生物学的重要性。
