GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE305nnn/GSE305096/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE305096GEOGSEfalseDNAJ-PKAc Induces Metabolic Rewiring and a Glutamine Dependency in Fibrolamellar HCCBackground: 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.2026/05/15GSE305096GSM9162200GSM9162202GSM9162201GSM9162204GSM9162203GSM916220524247305096Mus musculus[41205756]