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首页> 外文期刊>Oncogene >EGFR mutants found in non-small cell lung cancer show different levels of sensitivity to suppression of Src: implications in targeting therapy
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EGFR mutants found in non-small cell lung cancer show different levels of sensitivity to suppression of Src: implications in targeting therapy

机译：在非小细胞肺癌中发现的EGFR突变体显示出不同程度的抑制Src敏感性：在靶向治疗中的意义

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Mutations in epidermal growth factor receptor (EGFR) kinase domain associate with clinical responses to EGFR inhibitors and are frequently observed in non-small cell lung cancer (NSCLC) patients in East Asian populations. Clinically identified EGFR mutations cause constitutive receptor activation. The activating mechanisms were unclear but appeared to be different among EGFR mutants. We found that EGFR mutants had different sensitivity to an Src inhibitor PP2. S768I and L861Q mutants were less sensitive to Src suppression than others. Mutation at tyrosine 869 (845) residue, an Src phosphorylation site, decreased the phosphorylation levels of wild-type EGFR and other mutants, but not that of S768I and L861Q mutants, suggesting that S768I and L861Q mutants became Src independent for their activation and biological functions. In contrast, cells expressing EGFR-L858R or exon 19 deletion mutants were more sensitive to PP2 than cells expressing wild-type EGFR. Interestingly, EGFR with exon 19-deletion/T790M double mutations, which was resistant to gefitinib, remained sensitive to PP2. Taken together, our data indicate that Src inhibitors might be effective in treating NSCLC harboring specific types of EGFR mutations.
机译：表皮生长因子受体（EGFR）激酶结构域的突变与对EGFR抑制剂的临床反应相关，并且经常在东亚人群的非小细胞肺癌（NSCLC）患者中观察到。临床鉴定的EGFR突变引起组成型受体激活。激活机制尚不清楚，但在EGFR突变体之间似乎有所不同。我们发现EGFR突变体对Src抑制剂PP2具有不同的敏感性。 S768I和L861Q突变体对Src抑制的敏感性低于其他突变体。酪氨酸869（845）残基的突变（一个Src磷酸化位点）降低了野生型EGFR和其他突变体的磷酸化水平，但没有降低S768I和L861Q突变体的磷酸化水平，这表明S768I和L861Q突变体变得独立于Src的激活和生物学作用职能。相反，表达EGFR-L858R或外显子19缺失突变体的细胞比表达野生型EGFR的细胞对PP2更敏感。有趣的是，对吉非替尼具有抗性的带有外显子19缺失/ T790M双突变的EGFR仍然对PP2敏感。两者合计，我们的数据表明Src抑制剂可能有效治疗具有特定类型的EGFR突变的NSCLC。

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