Abstract B038: Vertical RAS-pathway inhibition in pancreatic cancer drives therapeutically exploitable mitochondrial alterations

Abstract Oncogenic KRAS mutations drive metabolic rewiring in pancreatic ductal adenocarcinoma (PDAC). Src-homology 2 domain-containing phosphatase 2 (SHP2) is essential for full KRAS activity and promising dual SHP2/mitogen-activated protein kinase (MAPK) inhibition is currently being tested in clinical trials. Exploitable metabolic adaptations may contribute to an invariably evolving resistance.To understand the metabolic changes induced by dual inhibition, we comprehensively tested cell lines, endogenous tumor models, and patient-derived organoids representing the full spectrum of PDAC molecular subtypes.We find that dual SHP2/mitogen-activated protein kinase kinase (MEK1/2) inhibition induces major mitochondrial alterations, elevates reactive oxygen species (ROS) levels and triggers a lipid peroxidase dependency. Anabolic pathways, autophagy and glycolysis were also profoundly altered. But most strikingly, mitochondrial remodeling was evident, persisting into a therapy resistant state. The resulting vulnerability to induction of ferroptotic cell death via combination of vertical SHP2/MEK1/2 with glutathione peroxidase (GPX4) inhibition was confirmed with direct targeting of RAS and offers a metabolic leverage point to reinforce RAS-pathway interference for targeted PDAC treatment. Citation Format: Philipp Hafner, Steffen Keller, Xun Chen, Asma Alrawashdeh, Huda Jumaa, Friederike Nollmann, Solène Besson, Judith Kemming, Oliver Gorka, Tonmoy Das, Bismark Appiah, Ariane Lehmann, Mujia Li, Petya Apostolova, Bertram Bengsch, Robert Zeiser, Stefan Tholen, Oliver Schilling, Olaf Groß, Andreas Vlachos, Uwe Wittel, Dominik von Elverfeldt, Wilfried Reichardt, Melanie Börries, Geoffroy Andrieux, Guus Heynen, Stefan Fichtner-Feigl, Luciana Hannibal, Dietrich Ruess. Vertical RAS-pathway inhibition in pancreatic cancer drives therapeutically exploitable mitochondrial alterations [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(18_Suppl_3):Abstract nr B038.