Glucokinase (GCK) functions as a MYCN-induced metabolic enzyme in neuroendocrine prostate cancer that maintains lineage identity through a noncanonical protein kinase activity, forming a reciprocal phosphorylation loop with AKT1 in which AKT1 phosphorylates GCK at S373 while GCK phosphorylates AKT1 at S473, and pharmacological disruption of this GCK-AKT1 axis suppresses tumor growth and blocks neuroendocrine lineage reprogramming independently of GCK's glucose-phosphorylating activity.

Cancer cells frequently rewire their metabolism to sustain growth and survival under stress. Despite the critical role of metabolic adaptation in tumorigenesis, how specific metabolic enzymes regulate lineage plasticity remains unclear. Here, through FDG-PET imaging and transcriptomic analyses, we reveal markedly elevated glucose uptake in neuroendocrine prostate cancer (NEPC) and identify glucokinase (GCK) as a MYCN-induced metabolic enzyme. Beyond its metabolic role, GCK is indispensable for maintaining the neuroendocrine lineage of prostate cancer cells by establishing a functional circuit with AKT1 through reciprocal regulation—AKT1 binds and phosphorylates GCK at S373, whereas GCK phosphorylates AKT1 at S473. Pharmacological disruption of this AKT1-GCK axis suppresses tumor growth in NEPC mouse models and patient-derived xenografts. Altogether, our findings uncover both the metabolic and noncanonical kinase functions of GCK and establish the AKT1-GCK axis as a key link between metabolic reprogramming and neuroendocrine lineage transition in prostate cancer.