Abstract 6664: ATF4 is required for PanIN formation and PDAC via effects on nucleotide metabolism and suppression of p53 activity

Abstract Pancreatic ductal adenocarcinoma (PDAC) is increasing in incidence in western society and has a 5-year survival rate of less than 13% which while better than it was several years ago, remains one of the worst for all solid tumors. The development of KRAS inhibitors to block the activity of the dominant activated oncogene in human PDAC brings hope that the mortality rate will improve in the coming years. However, as these new therapeutics enter clinical trials, there is an expectation that resistance to KRAS inhibitors will emerge. Thus, the interrogation of additional pathways and the mechanisms of drug resistance are critical to expand the efficacy of KRAS inhibitors and promote patient survival. Our work focuses on the role of Activating Transcription Factor 4 (ATF4) in PDAC where an ATF4-like gene signature predicts worse survival outcomes for PDAC patients. We show here for the first time that conditional loss of Atf4 in acinar cells of the adult mouse pancreas prevents KRas-driven PDAC, such that neither pre-malignant pancreatic intra-epithelial neoplasia (PanIN) lesions nor PDAC develops over the lifetime of the animal. We also show that loss of Atf4 alone in pancreatic acinar cells (absent KRas activation) causes increased pancreatitis and marked pancreas shrinkage following treatment with cerulein. We show that loss of Atf4 in adult pancreatic acinar cells leads to DNA damage, induction of p53 (and both p21 and Bax) and increased cell death, that is exacerbated by cerulein treatment. The increased DNA damage was associated with nucleotide depletion and decreased levels of metabolites involved in 1C metabolism which we attribute to the observed loss of expression of Atf4 targets, such as Mthfd2. Together, our data point to a critical role for Atf4 in maintaining nucleotide pools necessary for tumor cell growth and that its loss promotes p53-dependent cell death preventing PDAC initiation and progression. Citation Format: Leah M. Ziolkowski, Kay F. Macleod. ATF4 is required for PanIN formation and PDAC via effects on nucleotide metabolism and suppression of p53 activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6664.