The Epidermal Growth Factor Receptor-L861Q Mutation Increases Kinase Activity without Leading to Enhanced Sensitivity Toward Epidermal Growth Factor Receptor Kinase Inhibitors
The Epidermal Growth Factor Receptor-L861Q Mutation Increases Kinase Activity without Leading to Enhanced Sensitivity Toward Epidermal Growth Factor Receptor Kinase Inhibitors
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DOI：
10.1097/jto.0b013e3182021f3e
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发表时间：
2011-02-01
影响因子：
20.4
通讯作者：
Duyster, Justus
中科院分区：
文献类型：
--
作者：
Kancha, Rama Krishna;Peschel, Christian;Duyster, Justus
简介：据报道，表皮生长因子受体（EGFR）激酶结构域中的突变（例如EGFR-L 858 R和EGFR-G719 S）可激活该激酶，并且还使一部分非小细胞肺癌患者对EGFR激酶抑制剂治疗敏感。然而，对于其他常见的点突变，如EGFR-L 861 Q，尚不清楚它们是否以及在多大程度上对吉非替尼和厄洛替尼敏感。到目前为止，还没有可靠的细胞分析比较在一个配体独立的方式固有的激酶活性和药物敏感性的未突变（野生型）和突变的EGFR激酶domain.Methods：为了克服这一障碍，我们引入L 858 R，G719 S，和L 861 Q的骨干EGFRvIII。EGFRvIII具有野生型激酶结构域，但通过在胞外domain.Results中的缺失以配体独立的方式激活：使用此工具，我们表明，L 861 Q突变显示增强的激酶活性和转化潜力相比，L 858 R，G719 S，也野生型EGFR激酶结构域。有趣的是，与L 858 R和G719 S突变相比，L 861 Q不会增加对临床使用的EGFR激酶抑制剂的药物敏感性。结论：在常见的EGFR-L 861 Q突变中，激酶结构域的激活与临床上批准的激酶抑制剂的增敏作用不偶联。因此，携带EGFR-L 861 Q的患者从吉非替尼/厄洛替尼治疗中获得的临床获益可能与携带EGFR-L 858 R和EGFR-G719 S突变的患者不同。使用不可逆的第二代激酶抑制剂（如WZ-4002）治疗可能是EGFR-L 861 Q患者未来的一个有吸引力的选择。
Introduction: Mutations in the epidermal growth factor receptor (EGFR) kinase domain such as EGFR-L858R and EGFR-G719S have been reported to activate the kinase and also sensitize a subset of patients with non-small cell lung cancer to EGFR kinase inhibitor treatment. Nevertheless, for other common point mutations such as EGFR-L861Q, it is unclear whether and to what extent they sensitize toward gefitinib and erlotinib. Thus far, there is no reliable cellular assay to compare in a ligand-independent manner intrinsic kinase activity and drug sensitivity of the unmutated (wild type) and mutated EGFR kinase domain.Methods: To overcome this obstacle, we introduced L858R, G719S, and L861Q into the backbone of EGFRvIII. EGFRvIII has a wild type-kinase domain but is activated in a ligand-independent manner through a deletion in the extracellular domain.Results: Using this tool, we show that the L861Q mutation displays enhanced kinase activity and transforming potential compared with L858R, G719S, and also to the wild type-EGFR kinase domain. Interestingly, L861Q does not increase drug sensitivity toward clinically used EGFR kinase inhibitors in contrast to the L858R and G719S mutation. In addition, we demonstrate that EGFR-L861Q could be effectively inhibited with the irreversible second-generation EGFR inhibitor WZ-4002.Conclusions: Thus, in the common EGFR-L861Q mutation, activation of the kinase domain is uncoupled from a sensitizing effect toward clinically approved kinase inhibitors. Therefore, patients with EGFR-L861Q may not have the same clinical benefit from gefitinib/erlotinib treatment as patients with EGFR-L858R and EGFR-G719S mutations. Treatment with irreversible second-generation kinase inhibitors such as WZ-4002 may be an attractive option in the future for patients with EGFR-L861Q.