The activation of SRC family kinases and focal adhesion kinase with the loss of the amplified, mutated EGFR gene contributes to the resistance to afatinib, erlotinib and osimertinib in human lung cancer cells.
The activation of SRC family kinases and focal adhesion kinase with the loss of the amplified, mutated EGFR gene contributes to the resistance to afatinib, erlotinib and osimertinib in human lung cancer cells.
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DOI：
10.18632/oncotarget.19982
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发表时间：
2017-09-19
期刊：
影响因子：
--
通讯作者：
Ono M
中科院分区：
文献类型：
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作者：
Murakami Y;Sonoda K;Abe H;Watari K;Kusakabe D;Azuma K;Kawahara A;Akiba J;Oneyama C;Pachter JA;Sakai K;Nishio K;Kuwano M;Ono M
第二代和第三代表皮生长因子受体（EGFR）酪氨酸激酶活性（EGFR- tkis）抑制剂正在改善非小细胞肺癌患者的治疗。在这里，我们建立了两个亚系（BR1-8和BR2-3）对第二代抑制剂阿法替尼（afatinib）具有耐药性，该抑制剂来自人类肺癌细胞系HCC827，该细胞系含有激活EGFR酪氨酸激酶活性的突变。这些阿法替尼耐药亚系对第一代EGFR-TKI吉非替尼和厄洛替尼耐药，以及第三代EGFR-TKI奥西替尼耐药。与具有EGFR基因扩增的亲代HCC827细胞相比，这些耐药亚群显示出多种EGFR家族蛋白水平显著降低，包括激活的突变EGFR，并且EGFR扩增完全丧失。与HCC827细胞相比，多激酶抑制剂达沙替尼治疗或SRC小干扰RNA转染在更大程度上抑制耐药亚群的细胞存活和AKT磷酸化。此外，与HCC827细胞相比，耐药细胞的迁移更大，并被达沙替尼或FAK抑制剂抑制。这些发现表明，当多种EGFR家族蛋白的表达大部分被消除时，SRC家族激酶（SFKs）和FAK的代偿激活支持阿法替尼耐药细胞的存活和迁移。靶向sfk和FAK的强效药物组合可能克服肺癌细胞对第二代TKIs的耐药性。
Second- and third-generation inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase activity (EGFR-TKIs) are improving the treatment of patients with non-small cell lung cancer. Here we established two sublines (BR1-8 and BR2-3) resistant to a second-generation inhibitor, afatinib, from the human lung cancer cell line HCC827 that harbors a mutation that activates the tyrosine kinase activity of EGFR. These afatinib-resistant sublines were resistant to first-generation EGFR-TKIs, gefitinib and erlotinib, and a third-generation EGFR-TKI, osimertinib. These resistant sublines showed markedly reduced levels of multiple EGFR family proteins, including the activated mutant EGFR, and complete loss of EGFR amplification as compared with their parental HCC827 cells harboring amplification of EGFR gene. Treatment with the multikinase inhibitor dasatinib or transfection with a SRC small interfering RNA inhibited cell survival and AKT phosphorylation in drug-resistant sublines to a greater extent compared with HCC827 cells. Further, the migration of drug-resistant cells was greater compared with that of HCC827 cells and was inhibited by dasatinib or an FAK inhibitor. These findings indicate that compensatory activation of SRC family kinases (SFKs) and FAK supports the survival and migration of afatinib-resistant cells when the expression of multiple EGFR family proteins was mostly abrogated. Combinations of potent drugs that target SFKs and FAK may overcome the resistance of lung cancer cells to second-generation TKIs.