Though kinase inhibitors are heavily investigated in clinic to combat advanced hepatocellular carcinoma (HCC), clinical outcomes are overall disappointing, which may result from the absence of kinase-addicted subsets in HCC. Recently, a combination strategy that simultaneously inhibits multiple kinases are increasingly appreciated in HCC treatment, yet it is challenged by the dynamic nature of kinase network. This study aims to identify kinase clusters that may cooperate to drive the malignant growth of HCC. We reveal that ALK, FGFR2 and EphA5 are the essential kinases that assembled into a functional cluster to sustain the viability of HCC cells through downstream AKT, ERK and p38 dependent signaling pathways. Their co-activation is associated with the poor prognosis for overall survival in about 13% of HCC patients. Therapeutically, combined inhibition of kinases inhibitors or targeting heat shock protein 90 (Hsp90) led to significant therapeutic response in vitro and in vivo.