Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors.
Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors.
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DOI：
10.1038/onc.2009.198
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发表时间：
2009-08
期刊：
影响因子：
8
通讯作者：
Gazdar, A. F.
中科院分区：
文献类型：
--
作者：
Gazdar, A. F.
关键词：
表皮生长因子受体酪氨酸激酶抑制剂（EGFR TKI）吉非替尼和厄洛替尼是EGFR酪氨酸激酶结构域的可逆竞争性抑制剂，与EGFR的5′-三磷酸腺苷结合位点结合。EGFR基因的体细胞激活突变、基因拷贝数增加以及某些临床和病理学特征与这些药物在非小细胞肺癌（NSCLC）患者中的显著肿瘤缓解和良好临床结局相关。赋予EGFR TKI敏感性的特定类型激活突变存在于EGFR基因的酪氨酸激酶（TK）结构域中。外显子19缺失突变和外显子21中的单点取代突变L 858 R在NSCLC中最常见，被称为“经典”突变。对EGFR TKI不敏感的NSCLC肿瘤包括由KRAS和MET癌基因驱动的肿瘤。大多数最初对吉非替尼和厄洛替尼有反应的患者最终变得耐药并经历疾病进展。点突变T790 M约占这些获得性耐药病例的一半。目前正在对各种第二代EGFR TKI进行评价，由于其对受体TK结构域的不可逆抑制作用，可能具有克服T790 M介导的耐药性的潜力。
The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), gefitinib and erlotinib, are reversible competitive inhibitors of the tyrosine kinase domain of EGFR that bind to its adenosine-5′ triphosphate-binding site. Somatic activating mutations of the EGFR gene, increased gene copy number and certain clinical and pathological features have been associated with dramatic tumor responses and favorable clinical outcomes with these agents in patients with non-small-cell lung cancer (NSCLC). The specific types of activating mutations that confer sensitivity to EGFR TKIs are present in the tyrosine kinase (TK) domain of the EGFR gene. Exon 19 deletion mutations and the single-point substitution mutation L858R in exon 21 are the most frequent in NSCLC and are termed ‘classical’ mutations. The NSCLC tumors insensitive to EGFR TKIs include those driven by the KRAS and MET oncogenes. Most patients who initially respond to gefitinib and erlotinib eventually become resistant and experience progressive disease. The point mutation T790M accounts for about one half of these cases of acquired resistance. Various second-generation EGFR TKIs are currently being evaluated and may have the potential to overcome T790M-mediated resistance by virtue of their irreversible inhibition of the receptor TK domain.
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影响因子：
158.5
作者：
Lynch, TJ;Bell, DW;Haber, DA
通讯作者：
Haber, DA
影响因子：
8.8
作者：
Bianco, R.;Garofalo, S.;Rosa, R.;Damiano, V.;Gelardi, T.;Daniele, G.;Marciano, R.;Ciardiello, F.;Tortora, G.
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影响因子：
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作者：
Eberhard, DA;Johnson, BE;Hillan, KJ
通讯作者：
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DOI：
10.1073/pnas.0502860102
发表时间：
2005-05-24
影响因子：
11.1
作者：
Kwak, EL;Sordella, R;Haber, DA
通讯作者：
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影响因子：
158.5
作者：
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通讯作者：
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