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EGFR tyrosine kinase inhibition induces autophagy in cancer cells

机译：EGFR酪氨酸激酶抑制作用诱导癌细胞自噬

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The epidermal growth factor receptor (EGFR) signaling pathway is frequently dysregulated in a variety of human malignancies. As a result, agents have been developed to selectively inhibit the tyrosine kinase function of EGFR (EGFRTKI) for cancer therapy. However, the clinical efficacy of these drugs to date has been limited by both acquired and intrinsic resistance. Macroautophagy, a process of intracellular proteolysis, has been shown to be activated in response to EGFR targeted therapy. However, the specific role of the induction of autophagy remains controversial. Here we show that autophagy is induced in a dose-dependent manner by in vitro treatment of multiple cancer cell lines with EGFR-TKI. Additionally, we find that in cells highly resistant to EGFR-TKI, autophagy is not robustly activated and that co-treatment of these cells with rapamycin, a known inducer of autophagy, can partially restore sensitivity to EGFR-TKI. Finally, we demonstrate that, in resistant cell lines, EGFR-TKI sensitivity can be further inhibited by siRNA-mediated depletion of the critical autophagy protein ATG7. Thus, our data suggests that defective autophagy may be an EGFR-TKI resistance mechanism and that activation of autophagy may be a viable strategy to augment the cytotoxic effect of EGFR-TKIs.
机译：在多种人类恶性肿瘤中，表皮生长因子受体（EGFR）信号传导途径经常失调。结果，已开发出试剂以选择性抑制EGFR（EGFRTKI）的酪氨酸激酶功能以用于癌症治疗。然而，迄今为止，这些药物的临床疗效受到获得性和内在抗性的限制。巨噬细胞吞噬是一种细胞内蛋白水解过程，已被证明可响应EGFR靶向治疗而被激活。但是，自噬诱导的具体作用仍存在争议。在这里，我们显示通过吞噬EGFR-TKI对多种癌细胞系进行体外治疗，以剂量依赖性方式诱导自噬。此外，我们发现在对EGFR-TKI具有高度抗性的细胞中，自噬并没有被强烈激活，并且这些细胞与雷帕霉素（一种自噬的诱导剂）共同处理可以部分恢复对EGFR-TKI的敏感性。最后，我们证明，在耐药细胞系中，可通过siRNA介导的关键自噬蛋白ATG7的耗竭来进一步抑制EGFR-TKI敏感性。因此，我们的数据表明自噬缺陷可能是EGFR-TKI的耐药机制，自噬激活可能是增强EGFR-TKIs细胞毒性作用的可行策略。

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