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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 invariably evolving resistance. To understand the metabolic changes induced by dual inhibition, we comprehensively tested human and murine PDAC cell lines, endogenous tumor models, and patient-derived organoids, which are representative of the full spectrum of PDAC molecular subtypes. We found that dual SHP2\/mitogen-activated protein kinase kinase (MEK1\/2) inhibition induces major alterations in mitochondrial mass and function, impacts reactive oxygen species (ROS) homeostasis and triggers lipid peroxidase dependency. Anabolic pathways, autophagy and glycolysis were also profoundly altered. However, most strikingly, mitochondrial remodeling was evident, persisting into a therapy-resistant state. The resulting vulnerability to the induction of ferroptotic cell death via the combination of vertical SHP2\/MEK1\/2 with glutathione peroxidase (GPX4) inhibition was largely independent of the PDAC molecular subtype and was confirmed with direct targeting of RAS. The triple combination of SHP2\/MEK1\/2 inhibition and the ferroptosis-inducing natural compound withaferin A suppressed tumor progression in an endogenous PDAC tumor model in vivo. Our study offers a metabolic leverage point to reinforce RAS pathway interference for targeted PDAC treatment.<\/jats:p>","DOI":"10.1038\/s41392-025-02563-7","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:02:21Z","timestamp":1768568541000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Vertical RAS pathway inhibition in pancreatic cancer drives therapeutically exploitable mitochondrial alterations"],"prefix":"10.1038","volume":"11","author":[{"given":"Philipp","family":"Hafner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen 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