Abstract A007: ATF4 is required for KRas-driven pancreatic tumorigenesis to suppress early-stage p53 induction

Abstract The integrated stress response (ISR) is an adaptive cellular response system activated by nutrient deprivation, mitochondrial dysfunction, protein misfolding and other stresses that acts to restore cellular homeostasis by inducing expression of genes involved in amino acid metabolism, ER proteostasis, autophagy and other pathways that mitigate against the imposed stresses. At a molecular level, activation of the ISR converges on phosphorylation of eIF2a, silencing of cap-dependent protein translation and selective activation of the ATF4 transcription factor, that induces expression of genes involved in serine metabolism (eg. PSAT1, PHGDH), one-carbon metabolism (eg. MTHFD2, SHMT2), redox stress responses (eg. CHAC1, HMOX1) and others. Recent work has identified an ATF4-like gene expression signature (GEP14) in sc-RNA-Seq data from human pancreatic ductal adenocarcinoma (PDAC) patients as being predictive of worse survival outcomes across all PDAC sub-types and stages and most highly prognostic of patient survival in early-stage basal-like PDAC (Liu et al, 2025). To better understand the role of ATF4 in pancreatic tumorigenesis, we generated a novel genetically engineered mouse of PDAC in which Atf4 is selectively deleted in acinar cells of the adult mouse pancreas in the context of cerulein-induced pancreatitis or activation of oncogenic KRasG12D. Our work using these models defines a novel role for Atf4 in protecting against pancreatitis and PanIN/PDAC development by preventing p53-dependent cell death downstream of nutrient deprivation and DNA damage. Strikingly, acinar-specific deletion of Atf4 completely inhibits KRasG12D driven PanIN formation and PDAC in KC mice and is associated with elevated DNA damage and p53 levels as tumor initiate. This inhibition of PanIN and PDAC formation following Atf4 deletion extends the lifespan of KC mice to 2 years and is associated with lipid accumulation in the pancreas which remains functional throughout. PDAC tumorigenesis in KCA mice is rescued by deletion of p53 in KPCA mice that now develop PDAC. This work identifies ATF4 for the first time as a key suppressor of p53 induction at early stages of KRas-driven transformation of acinar cells, thereby allowing pre-malignant PanIN lesions to develop and survive which would otherwise be primed to undergo p53-dependent cell death. The failure to form PanIN lesions when Atf4 is deleted thereby prevents PDAC at a stage prior to selection for p53 inactivation and identifies ATF4 and/or key target genes as potential therapeutic targets to prevent pancreas cancer. Citation Format: Leah M. Ziolkowski, Tatsuki Ueda, Nicholas Chevrier, Hardik Shah, Kay F. Macleod. ATF4 is required for KRas-driven pancreatic tumorigenesis to suppress early-stage p53 induction abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr A007.