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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.

hepatology

Identification and Therapeutic Intervention of Coactivated Anaplastic Lymphoma Kinase, Fibroblast Growth Factor Receptor 2, and Ephrin Type‐A Receptor 5 Kinases in Hepatocellular Carcinoma