Vertical RAS pathway inhibition in pancreatic cancer drives therapeutically exploitable mitochondrial alterations PMID: 41545339

ADC Targets in Oncology

2026-04-10

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

Signal Transduct Target Ther. 2026 Jan 16;11(1):33. doi: 10.1038/s41392-025-02563-7.

Philipp Hafner ¹ ² , Steffen J Keller ¹ ² , Xun Chen ¹ ³ , Asma Alrawashdeh ¹ ² , Huda Jumaa ¹ , Friederike I Nollmann ¹ , Solène Besson ¹ , Judith Kemming ¹ ² , Oliver Gorka ⁴ , Tonmoy Das ⁵ , Bismark Appiah ⁵ , Ariane Lehmann ² ⁵ , Mujia Li ⁶ , Petya Apostolova ⁷ , Bertram Bengsch ⁸ ⁹ ¹⁰ , Robert Zeiser ⁹ ¹⁰ ¹¹ , Stefan Tholen ⁶ , Oliver Schilling ⁶ , Olaf Groß ⁴ ⁹ , Andreas Vlachos ¹² , Uwe A Wittel ¹ , Dominik von Elverfeldt ¹³ , Wilfried Reichardt ¹³ , Melanie Boerries ⁵ ¹⁰ , Geoffroy Andrieux ⁵ , Guus J Heynen ¹⁴ , Stefan Fichtner-Feigl ¹ , Luciana Hannibal ⁹ ¹⁵ , Dietrich A Ruess ¹⁶ ¹⁷

Affiliations

1. Department of General and Visceral Surgery, Center for Surgery, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany.
2. Faculty of Biology, University of Freiburg, Freiburg, Germany.
3. Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.
4. Institute of Neuropathology, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany.
5. Institute of Medical Bioinformatics and Systems Medicine, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany.
6. Institute of Surgical Pathology, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany.
7. Division of Hematology, University Hospital Basel, Basel, Switzerland.
8. Department of Internal Medicine II, Medical Center - University of Freiburg, Freiburg, Germany.
9. CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
10. German Cancer Consortium (DKTK), Partner site Freiburg, a partnership between DKFZ and Medical Center - University of Freiburg, Freiburg, Germany.
11. Department of Medicine I, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany.
12. Faculty of Medicine, Department of Neuroanatomy - University of Freiburg, Freiburg, Germany.
13. Division of Medical Physics, Department of Diagnostic and Interventional Radiology, Faculty of Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
14. Berlin Center for Advanced Therapies (BeCAT), Charité - Universitätsmedizin Berlin, Berlin, Germany.
15. Department of Pediatrics, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany.
16. Department of General and Visceral Surgery, Center for Surgery, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany. [email protected].
17. German Cancer Consortium (DKTK), Partner site Freiburg, a partnership between DKFZ and Medical Center - University of Freiburg, Freiburg, Germany. [email protected].

Abstract

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 model in vivo. Our study offers a metabolic leverage point to reinforce Ras pathway interference for targeted PDAC treatment.