EGFR tyrosine kinase inhibition induces autophagy in cancer cells
EGFR tyrosine kinase inhibition induces autophagy in cancer cells
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DOI：
10.4161/cbt.22002
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发表时间：
2012-12-01
影响因子：
3.6
通讯作者：
Duvvuri, Umamaheswar
中科院分区：
文献类型：
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作者：
Fung, Christopher;Chen, Xing;Duvvuri, Umamaheswar
表皮生长因子受体（EGFR）信号通路在多种人类恶性肿瘤中经常失调。因此，已经开发出选择性抑制EGFR酪氨酸激酶功能的药物（EGFR- tki）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耐药性的限制。巨噬，一种细胞内蛋白水解过程，已被证明在EGFR靶向治疗下被激活。然而，诱导自噬的具体作用仍然存在争议。本研究表明，EGFR-TKI在体外治疗多种癌细胞系时，自噬以剂量依赖的方式诱导。此外，我们发现在对EGFR-TKI具有高度抗性的细胞中，自噬并没有被强有力地激活，这些细胞与雷帕霉素（一种已知的自噬诱导剂）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，sirna介导的关键自噬蛋白ATG7的缺失可以进一步抑制EGFR-TKI敏感性。因此，我们的数据表明，有缺陷的自噬可能是EGFR-TKI耐药机制，激活自噬可能是增强EGFR-TKI细胞毒性作用的可行策略。
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 (EGFR-TKI) 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.