EGFR mutants found in non-small cell lung cancer show different levels of sensitivity to suppression of Src: implications in targeting therapy
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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DOI：
10.1038/sj.onc.1210684
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发表时间：
2008-02-07
期刊：
影响因子：
8
通讯作者：
Chen, Y-R
中科院分区：
文献类型：
--
作者：
Fu, Y-N;Yeh, C-L;Chen, Y-R
表皮生长因子受体（EGFR）激酶结构域突变与EGFR抑制剂的临床应答相关，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突变导致组成型受体活化。激活机制尚不清楚，但似乎是不同的EGFR突变体。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抑制的敏感性较低。酪氨酸869（845）残基（Src磷酸化位点）的突变降低了野生型EGFR和其他突变体的磷酸化水平，但不降低S768 I和L861 Q突变体的磷酸化水平，这表明S768 I和L861 Q突变体的激活和生物学功能变得不依赖于Src。相比之下，表达EGFR-L858 R或19号外显子缺失突变体的细胞比表达野生型EGFR的细胞对PP 2更敏感。有趣的是，对吉非替尼耐药的19号外显子缺失/T790M双突变EGFR对PP2仍然敏感。总之，我们的数据表明Src抑制剂可能有效治疗携带特定类型EGFR突变的NSCLC。
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.