The resistance of lung cancer to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is one of the unconquered frontiers in chemotherapy. Mitogen-inducible gene 6 (Mig-6) is known to inhibit the kinase activity of epidermal growth factor receptor (EGFR). Similarly, numerous studies of mouse models suggested tumor suppressive function of Mig-6 in lung cancer. On the contrary, the results of clinical investigations revealed that lung cancer patients with elevated expression of Mig-6 are associated with a poor prognosis. More recent work showed that unlike wild type (WT) EGFR, mutant EGFR phosphorylates Mig-6 and phosphorylated Mig-6 negatively regulates the degradation of EGFR mutants in lung adenocarcinoma. Here, we tried to untangle the controversies surrounding Mig-6 function as a protagonist or an antagonist of EGFR-TKI resistant lung cancer. We compared the expression and phosphorylation status of Mig-6 in the EGFR-TKI resistant lung adenocarcinoma (PC9/GR cells) to EGFR-TKI sensitive lung adenocarcinoma (PC9 cells). We investigated the function of Mig-6 by either depletion or overexpression of Mig-6 in those cells and evaluated the efficacy of combining of Mig-6 knock-down and EGFR-TKI treatment in PC9/GR. The correlation between Mig-6 expressions and the prognoses of lung adenocarcinoma was examined by The Cancer Genome Atlas (TCGA) data and clinical samples. Our results indicated that the expression of Mig-6 was significantly increased in PC9/GR cells compared to that of PC9 cells. The significant portion of Mig-6 existed as a phosphorylated form in PC9 and PC9/GR cells. Moreover, overexpression of Mig-6 significantly increased the cell proliferation, invasion and epithelial mesenchymal transition (EMT) in PC9 cells. Combination of Mig-6 knock-down and EGFR-TKI treatment significantly overcame the EGFR-TKI resistance of PC9/GR cells. In addition, our analyses of clinical samples confirmed that high Mig-6 expressions positively correlate with a poor prognosis and EGFR-TKI resistance in lung adenocarcinoma. Our findings reinforce scientific notion of Mig-6 as an oncoprotein in the context of EGFR-TKI resistant lung adenocarcinoma. We propose that targeting Mig-6 may be a promising strategy to overcome the EGFR-TKI resistance in lung cancer.

中文翻译：

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Mig-6的抑制克服了肺腺癌获得性的EGFR-TKI耐药性。

肺癌对表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）的耐药性是化疗领域不可战胜的领域之一。已知有丝分裂原诱导基因6（Mig-6）抑制表皮生长因子受体（EGFR）的激酶活性。同样，许多小鼠模型研究表明Mig-6在肺癌中具有抑制肿瘤的功能。相反，临床研究的结果表明，Mig-6表达升高的肺癌患者预后较差。最近的研究表明，与野生型（WT）EGFR不同，突变型EGFR使Mig-6磷酸化，而磷酸化的Mig-6负调节肺腺癌中EGFR突变体的降解。这里，我们试图阐明围绕Mig-6作为EGFR-TKI耐药性肺癌的主角或拮抗剂的功能的争议。我们比较了Mig-6在EGFR-TKI耐药性肺腺癌（PC9 / GR细胞）和EGFR-TKI敏感型肺腺癌（PC9细胞）中的表达和磷酸化状态。我们通过在这些细胞中耗竭或过表达Mig-6来研究Mig-6的功能，并评估了PC9 / GR中Mig-6敲除和EGFR-TKI治疗相结合的功效。通过癌症基因组图谱（TCGA）数据和临床样本检查了Mig-6表达与肺腺癌预后之间的相关性。我们的结果表明，与PC9细胞相比，Mig-6在PC9 / GR细胞中的表达显着增加。Mig-6的重要部分以磷酸化形式存在于PC9和PC9 / GR细胞中。此外，Mig-6的过表达显着增加PC9细胞中的细胞增殖，侵袭和上皮间质转化（EMT）。Mig-6敲除和EGFR-TKI治疗的结合显着克服了PC9 / GR细胞的EGFR-TKI耐药性。此外，我们对临床样品的分析证实，Mig-6高表达与肺腺癌的不良预后和EGFR-TKI耐药性正相关。我们的发现加强了在EGFR-TKI耐药性肺腺癌中Mig-6作为癌蛋白的科学认识。我们建议靶向Mig-6可能是克服肺癌中EGFR-TKI耐药性的一种有前途的策略。Mig-6的过表达显着增加PC9细胞中的细胞增殖，侵袭和上皮间质转化（EMT）。Mig-6敲除和EGFR-TKI治疗的结合显着克服了PC9 / GR细胞的EGFR-TKI耐药性。此外，我们对临床样品的分析证实，Mig-6高表达与肺腺癌的不良预后和EGFR-TKI耐药性正相关。我们的发现加强了在EGFR-TKI耐药性肺腺癌中Mig-6作为癌蛋白的科学认识。我们建议靶向Mig-6可能是克服肺癌中EGFR-TKI耐药性的一种有前途的策略。Mig-6的过表达显着增加PC9细胞中的细胞增殖，侵袭和上皮间质转化（EMT）。Mig-6敲除和EGFR-TKI治疗的结合显着克服了PC9 / GR细胞的EGFR-TKI耐药性。此外，我们对临床样品的分析证实，Mig-6高表达与肺腺癌的不良预后和EGFR-TKI耐药性正相关。我们的发现加强了在EGFR-TKI耐药性肺腺癌中Mig-6作为癌蛋白的科学认识。我们建议靶向Mig-6可能是克服肺癌中EGFR-TKI耐药性的一种有前途的策略。Mig-6敲除和EGFR-TKI治疗的结合显着克服了PC9 / GR细胞的EGFR-TKI耐药性。此外，我们对临床样品的分析证实，Mig-6高表达与肺腺癌的不良预后和EGFR-TKI耐药性正相关。我们的发现加强了在EGFR-TKI耐药性肺腺癌中Mig-6作为癌蛋白的科学认识。我们建议靶向Mig-6可能是克服肺癌中EGFR-TKI耐药性的一种有前途的策略。Mig-6敲除和EGFR-TKI治疗的结合显着克服了PC9 / GR细胞的EGFR-TKI耐药性。此外，我们对临床样品的分析证实，Mig-6高表达与肺腺癌的不良预后和EGFR-TKI耐药性正相关。我们的发现加强了在EGFR-TKI耐药性肺腺癌中Mig-6作为癌蛋白的科学认识。我们建议靶向Mig-6可能是克服肺癌中EGFR-TKI耐药性的一种有前途的策略。