Relationship of EGFR mutations, expression, amplification, and polymorphisms to epidermal growth factor receptor inhibitors in the NC160 cell lines
Relationship of EGFR mutations, expression, amplification, and polymorphisms to epidermal growth factor receptor inhibitors in the NC160 cell lines
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DOI：
10.1158/1078-0432.ccr-07-0547
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发表时间：
2007-11-15
影响因子：
11.5
通讯作者：
Ratain, Mark J.
中科院分区：
文献类型：
--
作者：
Liu, Wanqing;Wu, Xiaolin;Ratain, Mark J.
目的：对表皮生长因子受体（EGFR）抑制剂的敏感性和耐药性机制尚未完全了解，特别是在非小细胞肺癌（NSCLC）以外的癌症中。为了了解对此类药物的不同反应，我们使用了NCI 60癌细胞系。我们的目的是确定是否有EGFR的表达，突变，多态性和基因扩增之间的相互作用，以及这些因素是否与变异性在响应EGFR inhibitors.Experimental Design：EGFRVIII和酪氨酸激酶（TK）域突变进行了检查在NC 160癌细胞系。对5个多态性位点进行了基因分型，分别为-216G/T、-191C/A、内含子1（CA）n、R497 K和2607 A/G。分别用高密度单核苷酸多态性芯片和实时荧光定量PCR检测EGFR扩增。这些结果与厄洛替尼和其他11种EGFR抑制剂的细胞毒性数据以及这些line.Results的其他公开数据相关：所有12种抑制剂的表现相似。在两株细胞中未发现EGFRVIII基因突变，但发现TK基因突变，两株突变细胞对所有抑制剂均不敏感。同时，反应与EGFR扩增无关，但与EGFR基因表达相关，尤其是在基因状态相对正常的细胞系中。EGFR表达与-216G/T多态性相关，与内含子1（CA）n多态性无关。-216 G/T和R497 K多态性的组合与药物responsibility.Conclusions弱相关：这些观察结果表明，除了TK突变，生殖系变异也可能有助于EGFR抑制剂的药效学，特别是当EGFR是遗传正常的。
Purpose: The mechanism of sensitivity and resistance to epidermal growth factor receptor (EGFR) inhibitors is incompletely understood, particularly in cancers other than non - small-cell lung cancer (NSCLC). To understand the variable response to this class of drugs, we used the NCI 60 cancer cell lines. We aimed to determine if there are interactions between EGFR expression, mutations, polymorphisms, and gene amplification, and whether these factors are associated with variability in response to EGFR inhibitors.Experimental Design: The EGFRVIII and tyrosine kinase (TK) domain mutations were examined in the NC160 cancer cell lines. Five polymorphisms, -216G/T, -191C/A, intron 1 (CA)n, R497K, and 2607A/G, were genotyped. EGFR amplification was also assessed with high-density sing single-nucleoticle polymorphism chip and real-time PCR, respectively. The results were correlated with cytotoxicity data for erlotinib and other 11 EGFR inhibitors, as well as other publicly available data for these lines.Results: All 12 inhibitors behaved similarly. No EGFRVIII but putative TK mutations in two cell lines were found. Both mutant cell lines were insensitive to all inhibitors. Meanwhile, response did not correlate with EGFR amplification but with EGFR gene expression, especially in the cell lines with relatively normal gene status. In addition, EGFR expression was associated with the -216G/T polymorphism but not with the intron 1 (CA) n polymorphism. A combination of -216G/T and R497 K polymorphisms was weakly associated with drug response.Conclusions: These observations suggest that in addition to TK mutations, germ-line variability may also contribute to the pharmacodynamics of EGFR inhibitors, particularly when EGFR is genetically normal.