Identification and Therapeutic Intervention of Coactivated Anaplastic Lymphoma Kinase, Fibroblast Growth Factor Receptor 2, and Ephrin Type-A Receptor 5 Kinases in Hepatocellular Carcinoma.
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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肝细胞癌中共激活的间变性淋巴瘤激酶、成纤维细胞生长因子受体 2 和肝配蛋白 A 型受体 5 激酶的鉴定和治疗干预
DOI：
10.1002/hep.29792
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发表时间：
2019-03
期刊：
影响因子：
--
通讯作者：
Geng M
中科院分区：
文献类型：
--
作者：
Wang X;Zhang M;Ping F;Liu H;Sun J;Wang Y;Shen A;Ding J;Geng M
虽然激酶抑制剂在临床上已被大量研究以对抗晚期肝细胞癌（HCC），但临床结局总体上令人失望，这可能是由于HCC患者中缺乏激酶成瘾亚群。最近，同时抑制多种激酶的策略在HCC治疗中越来越受到重视，但它们受到激酶网络动态性质的挑战。本研究的目的是确定簇激酶，可能合作，以推动肝癌的恶性生长。我们发现，间变性淋巴瘤激酶，成纤维细胞生长因子受体2和肝配蛋白A型受体5是组装成功能簇的基本激酶，通过下游蛋白激酶B依赖性，细胞外信号调节激酶依赖性和p38依赖性信号通路维持HCC细胞的活力。它们的共激活与约13%的HCC患者的总体生存预后不良相关。此外，它们的活性受到热休克蛋白90（Hsp90）的严格调节。因此，结合激酶抑制或靶向热休克蛋白90导致显着的治疗反应，在体外和体内。结论：我们的研究结果建立了一个范式，突出了间变性淋巴瘤激酶，成纤维细胞生长因子受体2和肝配蛋白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患者亚组的诊断和后续干预提供概念性的“联合治疗靶点”。
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.
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影响因子：
3.1
作者：
Galuppo, Roberto;Ramaiah, Dinesh;Ponte, Oscar Moreno;Gedaly, Roberto
通讯作者：
Gedaly, Roberto
影响因子：
11.5
作者：
Carlos Montero, Juan;Seoane, Samuel;Pandiella, Atanasio
通讯作者：
Pandiella, Atanasio
影响因子：
13.5
作者：
Llovet, Josep M.;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
3.4
作者：
Cheng W;Ainiwaer A;Xiao L;Cao Q;Wu G;Yang Y;Mao R;Bao Y
通讯作者：
Bao Y
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi