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首页> 美国卫生研究院文献>Wiley-Blackwell Online Open >Identification and Therapeutic Intervention of Coactivated Anaplastic Lymphoma Kinase Fibroblast Growth Factor Receptor 2 and Ephrin Type‐A Receptor 5 Kinases in Hepatocellular Carcinoma
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Identification and Therapeutic Intervention of Coactivated Anaplastic Lymphoma Kinase Fibroblast Growth Factor Receptor 2 and Ephrin Type‐A Receptor 5 Kinases in Hepatocellular Carcinoma

机译：肝细胞癌中共活化的间变性淋巴瘤激酶成纤维细胞生长因子受体2和Ephrin A型受体5激酶的鉴定和治疗干预

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Though kinase inhibitors have been heavily investigated in the clinic to combat advanced hepatocellular carcinoma (HCC), clinical outcomes have been disappointing overall, which may be due to the absence of kinase‐addicted subsets in HCC patients. Recently, strategies that simultaneously inhibit multiple kinases are increasingly appreciated in HCC treatment, yet they are challenged by the dynamic nature of the kinase networks. This study aims to identify clustered kinases that may cooperate to drive the malignant growth of HCC. We show that anaplastic lymphoma kinase, fibroblast growth factor receptor 2, and ephrin type‐A receptor 5 are the essential kinases that assemble into a functional cluster to sustain the viability of HCC cells through downstream protein kinase B–dependent, extracellular signal–regulated kinase–dependent, and p38‐dependent signaling pathways. Their coactivation is associated with poor prognosis for overall survival in about 13% of HCC patients. Moreover, their activities are tightly regulated by heat shock protein 90 (Hsp90). Thereby Combined kinase inhibition or targeting of heat shock protein 90 led to significant therapeutic responses both in vitro and in vivo. Conclusion: Our findings established a paradigm that highlights the cooperation of anaplastic lymphoma kinase, fibroblast growth factor receptor 2, and ephrin type‐A receptor 5 kinases in governing the growth advantage of HCC cells, which might offer a conceptual “combined therapeutic target” for diagnosis and subsequent intervention in a subgroup of HCC patients.
机译：尽管在临床上已对激酶抑制剂进行了深入研究以抗击晚期肝细胞癌（HCC），但总体而言，临床结果令人失望，这可能是由于HCC患者中缺少激酶可归因的亚型所致。最近，同时抑制多种激酶的策略在HCC治疗中受到越来越多的重视，但是它们却受到激酶网络动态特性的挑战。这项研究旨在确定可以协同驱动HCC恶性生长的簇状激酶。我们显示，间变性淋巴瘤激酶，成纤维细胞生长因子受体2和ephrin A型受体5是必需的激酶，这些激酶组装成一个功能簇，以通过下游蛋白激酶B依赖性，细胞外信号调节激酶维持HCC细胞的活力。依赖和p38依赖的信号通路。他们的共同激活与大约13％的HCC患者的整体生存预后不良有关。此外，它们的活性受到热激蛋白90（Hsp90）的严格调控。因此，结合激酶抑制或靶向热休克蛋白90在体外和体内均导致显着的治疗反应。结论：我们的发现建立了一个范式，突出了间变性淋巴瘤激酶，成纤维细胞生长因子受体2和ephrin A型受体5激酶在控制HCC细胞生长优势方面的合作，这可能为HCC细胞提供概念性的“联合治疗靶点”肝癌患者亚组的诊断和后续干预。

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