Induction of autophagy contributes to crizotinib resistance in ALK-positive lung cancer
Induction of autophagy contributes to crizotinib resistance in ALK-positive lung cancer
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DOI：
10.4161/cbt.28162
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发表时间：
2014-05-01
影响因子：
3.6
通讯作者：
Ren, Xingcong
中科院分区：
文献类型：
--
作者：
Ji, Cheng;Zhang, Li;Ren, Xingcong
使用ALK融合癌蛋白抑制剂克唑替尼（PF02341066）治疗ALK阳性非小细胞肺癌患者取得了令人印象深刻的临床疗效。然而，在大约一年的时间里，这种药物不可避免地会产生获得性耐药性，这限制了这种新型靶向治疗的治疗效果。在本研究中，我们发现克唑尼替耐药肺癌细胞可诱导自噬，并有助于耐药。我们观察到ALK在克唑替尼耐药肺癌细胞系H3122CR-1中下调，这与自噬诱导有因果关系。克唑替尼耐药程度与自噬活性相关。克唑替尼耐药H3122CR-1细胞自噬的激活涉及Akt/mTOR信号通路的改变。此外，我们证明了自噬抑制剂氯喹可以恢复H3122CR-1对克里唑替尼的敏感性，增强其对耐药肺癌的疗效。因此，调节自噬作为克服alk阳性肺癌获得性硝唑尼耐药的新策略值得探索。
Use of the inhibitor of ALK fusion onco-protein, crizotinib (PF02341066), has achieved impressive clinical efficacy in patients with ALK-positive non-small cell lung cancer. Nevertheless, acquired resistance to this drug occurs inevitably in approximately a year, limiting the therapeutic benefits of this novel targeted therapy. In this study, we found that autophagy was induced in crizonitib-resistant lung cancer cells and contributed to drug resistance. We observed that ALK was downregulated in the crizotinib-resistant lung cancer cell line, H3122CR-1, and this was causally associated with autophagy induction. The degree of crizotinib resistance correlated with autophagic activity. Activation of autophagy in crizotinib-resistant H3122CR-1 cells involved alteration of the Akt/mTOR signaling pathway. Furthermore, we demonstrated that chloroquine, an inhibitor of autophagy, could restore sensitivity of H3122CR-1 to crizotinib and enhance its efficacy against drug-resistant lung cancer. Thus, modulating autophagy may be worth exploring as a new strategy to overcome acquired crizonitib resistance in ALK-positive lung cancer.