Abstract 4176: Targeting KRAS selectively induce metabolic reprogramming in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease largely due to the lack of effective treatments that overcome the tumor drug resistance. Oncogenic KRAS mutations contribute to most PDAC and drive multiple metabolic pathways to promote tumor growth. Despite this predominant role of KRAS, the inhibition of KRAS/MAPK pathway often leads to resistance via mechanisms that remain unclear. Pharmacological inhibition of the KRAS/MAPK pathway produces varying and context-dependent responses in different phenotypes of pancreatic cancer cells. Specifically, while KRAS/MAPK inhibition using drugs such as MRTX1133 and Trametinib suppresses growth in some cell lines, the same treatment induces or does not alter the growth of other cell lines, and selectively impacted cell migration. Metabolic activity was suppressed in cells with inhibited growth but accelerated in cells where KRAS/MAPK inhibition promoted growth. Analysis of gene expression profile of human PDAC and KRAS-driven mouse tumors identified nutrient transporters that are upregulated upon KRAS induction, but further upregulated by KRAS inhibition. Our study reveals context-dependent response to KRAS inhibition in PDAC and suggests targeting nutrient transporters to overcome therapeutic resistance. Laiba Shiekh and Matthew Cheung contributed equally to this work. Citation Format: Matthew Cheung, Laiba Shiekh, Don-Gerard Conde, Chiamaka Ezeh, Zeribe Nwosu. Targeting KRAS selectively induce metabolic reprogramming 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 4176.