Ji Cheng, Zhang Li, Cheng Yan, Patel Raj, Wu Hao, Zhang Yi, Wang Mian, Ji Shundong, Belani Chandra P, Yang Jin-Ming, Ren Xingcong
Department of Pharmacology; Penn State Hershey Cancer Institute; The Pennsylvania State University College of Medicine and Milton S. Hershey Medical Center; Hershey, PA USA; Department of Respiratory Medicine; The First Affiliated Hospital of Soochow University; Suzhou, Jiangsu, PR China.
Department of Pharmacology; Penn State Hershey Cancer Institute; The Pennsylvania State University College of Medicine and Milton S. Hershey Medical Center; Hershey, PA USA.
Cancer Biol Ther. 2014 May;15(5):570-7. doi: 10.4161/cbt.28162. Epub 2014 Feb 20.
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.
间变性淋巴瘤激酶（ALK）融合癌蛋白抑制剂克唑替尼（PF02341066）在ALK阳性非小细胞肺癌患者中已取得了令人瞩目的临床疗效。然而，大约一年后不可避免地会出现对该药物的获得性耐药，限制了这种新型靶向治疗的疗效。在本研究中，我们发现克唑替尼耐药的肺癌细胞中诱导了自噬，并且自噬导致了耐药。我们观察到在克唑替尼耐药的肺癌细胞系H3122CR-1中ALK表达下调，这与自噬诱导存在因果关系。克唑替尼耐药程度与自噬活性相关。克唑替尼耐药的H3122CR-1细胞中自噬的激活涉及Akt/mTOR信号通路的改变。此外，我们证明自噬抑制剂氯喹可恢复H3122CR-1对克唑替尼的敏感性，并增强其对耐药肺癌的疗效。因此，调节自噬可能值得作为一种克服ALK阳性肺癌中获得性克唑替尼耐药的新策略进行探索。
