Protective autophagy decreases osimertinib cytotoxicity through regulation of stem cell-like properties in lung cancer
Protective autophagy decreases osimertinib cytotoxicity through regulation of stem cell-like properties in lung cancer
复制标题
保护性自噬通过调节肺癌干细胞样特性降低奥希替尼的细胞毒性
DOI：
10.1016/j.canlet.2019.03.027
复制
发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
He, Yong
中科院分区：
文献类型：
--
作者：
Li, Li;Wang, Yubo;He, Yong
Osimertinib是一种第三代表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)，对EGFR突变的非小细胞肺癌(NSCLC)有很好的疗效，但耐药是不可避免的。Osimertinib诱导NSCLC细胞自噬，但自噬在Osimertinib耐药中的作用尚不清楚。我们在体外和体内发现，增强的自噬与奥西美替尼的耐药性有关。抑制自噬增强了奥西美替尼对耐药细胞和敏感细胞的细胞毒性。此外，奥西美替尼耐药细胞表现出干细胞样的特性，而自噬抑制通过下调SOX2和ALDH1A1的表达来降低毒性。此外，我们发现，敲除Beclin-1抑制了干细胞样特性，并恢复了osimertinib的细胞毒性。在异种移植小鼠中，奥西莫替尼与氯喹联合使用比单独使用更有效地抑制肿瘤生长。这些结果表明，自噬通过诱导干细胞样属性在奥西莫替尼的细胞毒性中起着不利的作用。联合应用EGFR-TKI和自噬抑制剂可为提高奥西美替尼的细胞毒性提供一种有前景的策略。
Osimertinib, a third-generation epidermal growth factor receptor - tyrosine kinase inhibitor (EGFR-TKI), shows great efficacy in EGFR-mutant non-small cell lung cancer (NSCLC); however, the resistance is inevitable. Osimertinib induces autophagy in NSCLC cells, but the role of autophagy in osimertinib resistance is not clear. We discovered that enhanced autophagy is associated with osimertinib resistance in vitro and in vivo. Inhibition of autophagy enhanced osimertinib cytotoxicity in both osimertinib-resistant and sensitive cells. Moreover, osimertinib-resistant cells exhibited stem cell-like properties, whereas autophagy inhibition decreased the sternness by downregulating the expression of SOX2 and ALDH1A1. Further, we found that knockdown of Beclin-1 inhibited the stem cell-like properties and restored osimertinib cytotoxicity. Osimertinib combined with chloroquine inhibited tumor growth more effectively than alone in xenograft mice. These results reveal that autophagy plays an adverse role in osimertinib cytotoxicity through inducing stem cell-like properties. Combination therapy of EGFR-TKI and autophagy inhibitor could provide a promising strategy to improve osimertinib cytotoxicity.