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DNAJ-PKAc Induces Metabolic Rewiring and a Glutamine Dependency in Fibrolamellar HCC

ABSTRACT: Background: Fibrolamellar carcinoma (FLC) is a pediatric and adolescent liver cancer that is characterized by a recurrent fusion of DNAJB1 and PRKACA, yielding a chimeric translated protein, DNAJ-PKAc. PRKACA encodes the catalytic subunit of protein kinase A (PKA), a regulator of cellular metabolism. Methods: We generated a syngeneic murine model of FLC, TIBx-DNAJ-PKAc. We utilized preclinical models of FLC and human specimens to characterize the metabolic and immune effects of DNAJ-PKAc. Results: DNAJ-PKAc induced a high glycolytic flux and glutamine dependence to support nucleotide metabolism and redox homeostasis. TIBx-DNAJ-PKAc tumors demonstrated reduced T cell infiltration with impaired T cell activation. Systemic administration of a glutamine antagonist reversed the immune-inactivated phenotype of TIBx-DNAJ-PKAc tumors and provided durable control in combination with immune checkpoint inhibitors (ICI). Conclusion: The presence of DNAJ-PKAc creates a vulnerability to the combination of glutamine antimetabolite and ICI therapy in FLC.

ORGANISM(S): Mus musculus

PROVIDER: GSE305096 | GEO | 2026/05/15

REPOSITORIES: GEO

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