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一种小分子黏着斑激酶(FAK)抑制剂GSK2256098可抑制胰腺导管腺癌细胞的生长和存活。

A small molecule FAK kinase inhibitor, GSK2256098, inhibits growth and survival of pancreatic ductal adenocarcinoma cells.

作者信息

Zhang Jianliang, He Di-Hua, Zajac-Kaye Maria, Hochwald Steven N

机构信息

a Department of Surgical Oncology ; Roswell Park Cancer Institute ; Elm and Carlton Streets ; Buffalo , NY USA.

出版信息

Cell Cycle. 2014;13(19):3143-9. doi: 10.4161/15384101.2014.949550.

Abstract

Focal adhesion kinase (FAK) hyperactivation is common in pancreatic ductal adenocarcinoma (PDAC). A small molecule, GSK2256098 (GlaxoSmithKline), has been developed to inhibit FAK activity through targeting the phosphorylation site of FAK, tyrosine (Y) 397. We sought to determine whether GSK2256098 inhibition of FAK Y397 phosphorylation attenuates PDAC-associated cell proliferation, motility and survival. Cultured PDAC cells were used as cellular models of GSK2256098-impaired abnormal growth. Western blot analysis, cell viability analysis, clonogenic survival, soft-agar and wound healing assays were performed. The responses of 6 PDAC cell lines in regards to FAK Y397 phosphorylation or activity to GSK2256098 treatments (0.1-10 μM) ranged from low (less than 20% inhibition) to high (more than 90% inhibition). The least and most sensitive cell lines (PANC-1 and L3.6P1) were selected for further analysis. GSK2256098 inhibition of FAK Y397 phosphorylation correlated with decreased levels of phosphorylated Akt and ERK in L3.6P1 cells. GSK2256098 decreased cell viability, anchorage-independent growth, and motility in a dose dependent manner. Current studies demonstrate that small molecule kinase inhibitors targeting FAK Y397 phosphorylation can inhibit PDAC cell growth. Assessments of FAK Y397 phosphorylation in biopsies may be used as a biomarker to select the subgroup of responsive patients and/or monitor the effects of GSK2256098 on FAK-modulated tumor growth during treatment.

摘要

粘着斑激酶(FAK)的过度激活在胰腺导管腺癌(PDAC)中很常见。一种小分子化合物GSK2256098(葛兰素史克公司)已被开发出来,它通过靶向FAK的磷酸化位点酪氨酸(Y)397来抑制FAK活性。我们试图确定GSK2256098对FAK Y397磷酸化的抑制作用是否能减弱与PDAC相关的细胞增殖、运动能力和存活能力。培养的PDAC细胞被用作GSK2256098抑制异常生长的细胞模型。进行了蛋白质免疫印迹分析、细胞活力分析、克隆形成存活分析、软琼脂分析和伤口愈合分析。6种PDAC细胞系对GSK2256098处理(0.1 - 10 μM)的FAK Y397磷酸化或活性反应范围从低(抑制率小于20%)到高(抑制率大于90%)。选择了最不敏感和最敏感的细胞系(PANC - 1和L3.6P1)进行进一步分析。GSK2256098对FAK Y397磷酸化的抑制与L3.6P1细胞中磷酸化Akt和ERK水平的降低相关。GSK2256098以剂量依赖的方式降低细胞活力、非锚定依赖性生长和运动能力。目前的研究表明,靶向FAK Y397磷酸化的小分子激酶抑制剂可以抑制PDAC细胞生长。活检中FAK Y397磷酸化的评估可作为一种生物标志物,用于选择反应性患者亚组和/或监测GSK2256098在治疗期间对FAK调节的肿瘤生长的影响。

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