Vertical RAS pathway inhibition in pancreatic cancer drives therapeutically exploitable mitochondrial alterations

作者：Philipp Hafner, Steffen Johannes Keller, Xun Chen, Asma Y. Alrawashdeh, Huda Jumaa, Friederike Inga Nollmann, Solène Besson, Judith Kemming, Oliver Gorka, Tonmoy Das, Bismark Appiah, Ariane Lehmann, Mujia Jenny Li, Petya Apostolova, Bertram Bengsch, Robert Zeiser, Stefan Tholen, Oliver Schilling, O. Groß, Andreas Vlachos, Uwe A. Wittel, Dominik von Elverfeldt, Wilfried Reichardt, Melanie Boerries, Geoffroy Andrieux, Guus J.J.E. Heynen, Stefan Fichtner-Feigl, Luciana Hannibal, Dietrich Alexander Ruess · 发表于：Signal Transduction and Targeted Therapy · 年份：2026 · DOI：10.1038/s41392-025-02563-7 · 被引用次数：7 · 研究领域：Ferroptosis and cancer prognosis、Protein Tyrosine Phosphatases、FOXO transcription factor regulation

Oncogenic KRAS mutations drive metabolic reprogramming 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 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 mode...