Loss of activating EGFR mutant gene contributes to acquired resistance to EGFR tyrosine kinase inhibitors in lung cancer cells.
Loss of activating EGFR mutant gene contributes to acquired resistance to EGFR tyrosine kinase inhibitors in lung cancer cells.
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DOI：
10.1371/journal.pone.0041017
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Ono M
中科院分区：
文献类型：
--
作者：
Tabara K;Kanda R;Sonoda K;Kubo T;Murakami Y;Kawahara A;Azuma K;Abe H;Kage M;Yoshinaga A;Tahira T;Hayashi K;Arao T;Nishio K;Rosell R;Kuwano M;Ono M
携带表皮生长因子受体（EGFR）突变的非小细胞肺癌对EGFR-酪氨酸激酶抑制剂（TKI）的反应有意义。然而，对EGFR-TKI的获得性耐药可能影响几乎所有患者的长期结局。为了确定潜在的耐药机制，我们从携带激活EGFR突变的人肺癌细胞系PC 9和11 -18中建立了对EGFR-TKI耐药的细胞系。独立地建立了来自PC 9的一个厄洛替尼抗性细胞系和来自11-18的两个厄洛替尼抗性细胞系和两个吉非替尼抗性细胞系。在从PC 9分离的厄洛替尼耐药细胞中观察到突变型delE 746-A750 EGFR基因几乎完全丢失，并且在11-18的厄洛替尼和吉非替尼耐药细胞中特别观察到突变型L 858 R EGFR基因拷贝的部分丢失。然而，即使在所有耐药细胞系中突变的EGFR基因丢失后，即使在药物存在下，也观察到EGFR下游信号传导PI 3 K/Akt的组成型激活。在来自PC 9的厄洛替尼耐药细胞中，拉帕替尼（EGFR和HER 2的双重TKI）或BIBW 2992（EGFR家族蛋白的泛TKI）可有效抑制组成性PI 3 K/Akt活化。此外，通过其同源siRNA敲低HER 2或HER 3的厄洛替尼也抑制PI 3 K/Akt活化。激活突变EGFR互补DNA的转染恢复了厄洛替尼耐药细胞系的药物敏感性。我们的研究表明，对突变型EGFR的成瘾性丧失导致对HER 2/HER 3和PI 3 K/Akt信号转导的成瘾性获得，从而获得EGFR-TKI抗性。
Non-small-cell lung cancer harboring epidermal growth factor receptor (EGFR) mutations attains a meaningful response to EGFR-tyrosine kinase inhibitors (TKIs). However, acquired resistance to EGFR-TKIs could affect long-term outcome in almost all patients. To identify the potential mechanisms of resistance, we established cell lines resistant to EGFR-TKIs from the human lung cancer cell lines PC9 and11–18, which harbored activating EGFR mutations. One erlotinib-resistant cell line from PC9 and two erlotinib-resistant cell lines and two gefitinib-resistant cell lines from 11–18 were independently established. Almost complete loss of mutant delE746-A750 EGFR gene was observed in the erlotinib-resistant cells isolated from PC9, and partial loss of the mutant L858R EGFR gene copy was specifically observed in the erlotinib- and gefitinib-resistant cells from 11–18. However, constitutive activation of EGFR downstream signaling, PI3K/Akt, was observed even after loss of the mutated EGFR gene in all resistant cell lines even in the presence of the drug. In the erlotinib-resistant cells from PC9, constitutive PI3K/Akt activation was effectively inhibited by lapatinib (a dual TKI of EGFR and HER2) or BIBW2992 (pan-TKI of EGFR family proteins). Furthermore, erlotinib with either HER2 or HER3 knockdown by their cognate siRNAs also inhibited PI3K/Akt activation. Transfection of activating mutant EGFR complementary DNA restored drug sensitivity in the erlotinib-resistant cell line. Our study indicates that loss of addiction to mutant EGFR resulted in gain of addiction to both HER2/HER3 and PI3K/Akt signaling to acquire EGFR-TKI resistance.
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