A novel STAT3 inhibitor W2014-S regresses human non-small cell lung cancer xenografts and sensitizes EGFR-TKI acquired resistance.
A novel STAT3 inhibitor W2014-S regresses human non-small cell lung cancer xenografts and sensitizes EGFR-TKI acquired resistance.
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新型 STAT3 抑制剂 W2014-S 可消退人类非小细胞肺癌异种移植物并提高 EGFR-TKI 获得性耐药性
DOI：
10.7150/thno.49600
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发表时间：
2021
期刊：
影响因子：
12.4
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Zheng Q;Dong H;Mo J;Zhang Y;Huang J;Ouyang S;Shi S;Zhu K;Qu X;Hu W;Liu P;Wang Y;Zhang X
信号转导子和转录激活子3（STAT 3）的组成性激活是人非小细胞肺癌（NSCLC）的共同特征。STAT 3作为癌基因的驱动因子在肿瘤进展中发挥重要作用，作为一种替代性激活途径在靶向治疗的获得性耐药中发挥重要作用。W2014-S具有咪唑并吡啶（imidazopyridine）的药效团结构，首次被报道用于STAT 3抑制剂的发现。本研究旨在探讨W2014-S在NSCLC中的抗肿瘤活性和机制，以及对表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）耐药性的影响。研究方法：利用SPR分析、免疫共沉淀、共聚焦显微镜成像和荧光素酶报告基因测定来确定机制。使用细胞活力、集落存活、伤口愈合、细胞侵袭测定、人癌细胞异种移植物和PDX肿瘤异种移植物来确定抗肿瘤活性。结果：W2014-S阻断了NSCLC细胞中STAT 3的二聚化，并选择性抑制了STAT 3的异常信号转导。在小鼠模型中，W2014-S强烈抑制具有异常STAT 3活化的肺癌细胞的增殖、存活、迁移和侵袭，并抑制人NSCLC细胞异种移植物和PDX肿瘤异种移植物的生长。此外，W2014-S在体外对吉非替尼和厄洛替尼具有显著的致敏作用，并在体内增强吉非替尼在TKI耐药肺癌异种移植物中的抗肿瘤作用。结论：我们的研究提供了一种在NSCLC中具有显著抗肿瘤活性的新型STAT 3抑制剂，并表明STAT 3抑制剂如W2014-S与吉非替尼的组合可以作为克服NSCLC患者中EGFR-TKI获得性耐药的有希望的策略。
Constitutive activation of signal transducer and activator of transcription 3 (STAT3) is a common feature in human non-small cell lung cancer (NSCLC). STAT3 plays an important role in cancer progression as a driver oncogene and acquired resistance of targeted therapies as an alternatively activated pathway. W2014-S with pharmacophore structure of imidazopyridine, which was firstly reported to be utilized in STAT3 inhibitor discovery, was screened out as a potent STAT3 inhibitor from a library of small molecules. The aim of this study is to investigate the antitumor activities and mechanisms of W2014-S in NSCLC and effect on epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) resistance in vitro and in vivo. Methods: SPR analysis, Co-immunoprecipitation, confocal microscope imaging, and luciferase report gene assays were utilized to determine the mechanisms. Cell viability, colonial survival, wound healing, cell invasion assay, human cancer cell xenografts and PDX tumor xenografts were used to determine antitumor activities. Results: W2014-S disrupted STAT3 dimerization and selectively inhibited aberrant STAT3 signaling in NSCLC cell line. W2014-S strongly suppressed proliferation, survival, migration and invasion of lung cancer cells with aberrant STAT3 activation and inhibited the growth of human NSCLC cell xenografts and PDX tumor xenografts in mouse model. Furthermore, W2014-S significantly sensitized resistant NSCLC cell line to gefitinib and erlotinib in vitro and enhances the anti-tumor effect of gefitinib in TKI-resistant lung cancer xenografts in vivo. Conclusions: Our study has provided a novel STAT3 inhibitor with significant anti-tumor activities in NSCLC and suggests that combination of STAT3 inhibitor such as W2014-S with gefitinib could serve as a promising strategy to overcome EGFR-TKIs acquired resistance in NSCLC patients.
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DOI：
10.1097/jto.0b013e3181f38f70
发表时间：
2010-11
期刊：
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
影响因子：
--
作者：
Haura EB;Sommers E;Song L;Chiappori A;Becker A
通讯作者：
Becker A
核 PKM2 通过上调结直肠癌中 STAT3 的激活而导致吉非替尼耐药。
影响因子：
4.6
作者：
Li Q;Zhang D;Chen X;He L;Li T;Xu X;Li M
通讯作者：
Li M
影响因子：
50.3
作者：
Bai, Longchuan;Zhou, Haibin;Wang, Shaomeng
通讯作者：
Wang, Shaomeng
影响因子：
1.9
作者：
Mao, Yousheng;Yang, Ding;Krasna, Mark J.
通讯作者：
Krasna, Mark J.
通过抑制磷酸甘油酸脱氢酶克服 EGFR 突变阳性肺腺癌的厄洛替尼耐药性
影响因子：
12.4
作者：
Dong JK;Lei HM;Liang Q;Tang YB;Zhou Y;Wang Y;Zhang S;Li WB;Tong Y;Zhuang G;Zhang L;Chen HZ;Zhu L;Shen Y
通讯作者：
Shen Y