AB073. P045. Mutant GNAS drives pancreatic tumorigenesis via PKA-SIK signaling and reprogramming lipid metabolism

Abstract: G-protein α_s (GNAS) mediates receptor-stimulated cAMP signaling, a conserved pathway that integrates nutritional and hormonal cues with regulation of cellular metabolism. GNAS is mutationally activated in many human tumors, yet its oncogenic functions remain elusive. We investigated the functions of activated GNAS^R201C in pancreatic tumorigenesis where concurrent GNAS and KRAS mutations define an important pancreatic ductal adenocarcinoma (PDA) subset arising from intraductal papillary mucinous neoplasms (IPMNs). By developing genetically engineered mouse models (GEMMs), we show that GNAS^R201C cooperates with KRAS^G12D to drive initiation of IPMN, which progress to invasive PDA following Tp53 loss. Moreover, continued expression of mutant GNAS remains critical for tumor maintenance in both GEMMs and human PDA cells. Additionally, we demonstrate that tumor maintenance requires GNAS^R201C-mediated activation of protein kinase A (PKA) and resulting inhibition of the salt-inducible kinases (SIK1-3). This pathway reprograms cellular metabolism, potentiating lipid remodeling and fatty acid oxidation. Furthermore, comparison of KRAS mutant pancreatic cancer cells with and without GNAS mutations reveals striking differences in the circuitry and functional impact of this network. Thus, our studies uncover GNAS-driven oncogenic mechanisms, identify SIK kinases as potent tumor suppressors, and demonstrate unanticipated metabolic heterogeneity among KRAS-mutant pancreatic neoplasms.