Abstract 5132: DNMT1-associated EMT promotes KRAS escape in pancreatic cancer

Abstract Pancreatic adenocarcinoma (PDAC) is presently the 3rd leading cause of cancer death in the United States and is further projected to overcome colorectal cancer to become the 2nd leading cause by 2030. The genetic landscape of PDAC is characterized by pervasive oncogenic mutations in KRAS, observed in over 90% of PDAC tumors. KRAS is considered essential for maintaining tumor progression and so targeting it has long been considered crucial to improving outcomes for PDAC patients. For preclinical studies of KRAS in our lab, we are using an inducible KRAS (iKRAS) model to model KRAS activation and inhibition. This model is based on iKRAS cell lines derived from transgenic tetO_LSL-KrasG12D; p53L/+; p48-Cre mice and upon doxycycline treatment, express oncogenic KrasG12D. Orthotopic implantation of iKRAS cells results in the formation of doxycycline-dependent pancreatic tumor growth in both immune-deficient and immunocompetent models. Withdrawal of doxycycline results in tumor regression. However, we have observed instances of tumor relapse despite the absence of doxycycline and established cell lines from these relapsed tumors. In vitro analyses confirm that these cells are independent of both doxycycline and KRAS, unlike the parental cell line. In vivo, upon reimplantation in the pancreas, they maintain the ability to grow independently of doxycycline. Transcriptome and reverse phase protein array analysis reveal an enrichment of markers associated with epithelial to mesenchymal (EMT) with western blot analyses further confirming increased expression of EMT markers, including Snail, Slug, and αSMA. The KRAS-independent cell line further demonstrated elevated DNMT1 expression, a previously described driver of EMT. Targeting DMNT demonstrated more pronounced effects on cell viability in the KRAS-independent cell line than the parental KRAS-dependent cell line. Deeper insight into the ability of these cells to escape KRAS addiction will enhance our understanding of resistance to KRAS inhibition and suggest further avenues for co-targeting. Citation Format: Loan Duong, Xin Lu. DNMT1-associated EMT promotes KRAS escape in pancreatic cancer [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 5132.