CT-707 Overcomes Resistance of Crizotinib through Activating PDPK1-AKT1 Pathway by Targeting FAK
CT-707 Overcomes Resistance of Crizotinib through Activating PDPK1-AKT1 Pathway by Targeting FAK
复制标题
CT-707通过靶向FAK激活PDPK1-AKT1通路克服克唑替尼耐药
DOI：
10.2174/1568009618666181031152140
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发表时间：
2019-01-01
影响因子：
3
通讯作者：
Han, Xiaohong
中科院分区：
文献类型：
--
作者：
Liang, Caixia;Zhang, Ningning;Han, Xiaohong
背景：克里佐替尼确立了间变性淋巴瘤蛋白酪氨酸激酶抑制剂(ALK-TKI)在非小细胞肺癌(NSCLC)治疗中的地位，但治疗耐药性阻碍了NSCLC患者继续受益。CT-707是碱性磷酸酶/粘着斑激酶(FAK)和IGFR-1的抑制剂。从亲本细胞株H2228(EML4-ALK，E6a/b：A20，变异体3)和H3122(EML4-ALK，E13：A20，变异体1)分别获得H2228CR(Crizotinib耐药，CR)和H3122CR NSCLC细胞系(H3122CR NSCLC)。同时，采用H3122CR体内移植瘤模型，发现CT-707对肿瘤生长有明显的抑制作用，且无明显副作用。结论：CT-707可能是治疗非小细胞肺癌耐药药的一种有前景的药物。
Background: Crizotinib established the position of anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKI) in the treatment of non-small cell lung cancer (NSCLC) while the therapy-resistance hindered those patients from benefitting continuously from the treatment. CT-707 is an inhibitor of ALK/focal adhesion kinase (FAK) and IGFR-1. H2228CR (crizotinib resistance, CR) and H3122CR NSCLC cell lines were generated from the parental cell line H2228 (EML4-ALK, E6a/b:A20, variant 3) and H3122(EML4-ALK, E13:A20, variant 1), respectively.Methods: We investigated the antitumor effects CT-707 exerted against H3122CR in vitro /vivo.Results: Importantly, our study provided evidence that CT-707 overcomes resistance to crizotinib not: through activating PDPK1 -AKT1 pathway by targeting FAK. Meanwhile, by using an in-vivo H3122CR xenograft model, we found CT-707 inhibited tumor growth significantly without obvious side effects.Conclusion: These findings indicate that CT-707 may be a promising therapeutic agent against crizotinib-resistance in NSCLC.