Z Gastroenterol 2025; 63(08): e543
DOI: 10.1055/s-0045-1810960
Abstracts | DGVS/DGAV
Kurzvorträge
Molekulare Mechanismen bei Pankreaskarzinom Donnerstag, 18. September 2025, 15:50 – 17:18, Seminarraum 6 + 7

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

P Hafner
1   Medical Center – University of Freiburg, Department of General and Visceral Surgery, Freiburg im Breisgau, Deutschland
,
S Keller
1   Medical Center – University of Freiburg, Department of General and Visceral Surgery, Freiburg im Breisgau, Deutschland
,
X Chen
1   Medical Center – University of Freiburg, Department of General and Visceral Surgery, Freiburg im Breisgau, Deutschland
,
A Alrawashdeh
1   Medical Center – University of Freiburg, Department of General and Visceral Surgery, Freiburg im Breisgau, Deutschland
,
H Jumaa
1   Medical Center – University of Freiburg, Department of General and Visceral Surgery, Freiburg im Breisgau, Deutschland
,
F Nollmann
1   Medical Center – University of Freiburg, Department of General and Visceral Surgery, Freiburg im Breisgau, Deutschland
,
S Besson
1   Medical Center – University of Freiburg, Department of General and Visceral Surgery, Freiburg im Breisgau, Deutschland
,
J Kemming
1   Medical Center – University of Freiburg, Department of General and Visceral Surgery, Freiburg im Breisgau, Deutschland
,
O Gorka
2   Medical Center – University of Freiburg, Institute of Neuropathology, Freiburg im Breisgau, Deutschland
,
T Das
3   Medical Center – University of Freiburg, Institute of Medical Bioinformatics and Systems Medicine, Freiburg im Breisgau, Deutschland
,
B Appiah
3   Medical Center – University of Freiburg, Institute of Medical Bioinformatics and Systems Medicine, Freiburg im Breisgau, Deutschland
,
A Lehmann
3   Medical Center – University of Freiburg, Institute of Medical Bioinformatics and Systems Medicine, Freiburg im Breisgau, Deutschland
,
M Li
4   Medical Center – University of Freiburg, Institute of Surgical Pathology,, Freiburg im Breisgau, Deutschland
,
P Apostolova
5   University Hospital Basel, Division of Hematology, Basel, Schweiz
,
B Bengsch
6   Medical Center – University of Freiburg, Department of Internal Medicine II, Freiburg im Breisgau, Deutschland
,
S Tholen
4   Medical Center – University of Freiburg, Institute of Surgical Pathology,, Freiburg im Breisgau, Deutschland
,
O Schilling
4   Medical Center – University of Freiburg, Institute of Surgical Pathology,, Freiburg im Breisgau, Deutschland
,
O Groß
2   Medical Center – University of Freiburg, Institute of Neuropathology, Freiburg im Breisgau, Deutschland
,
A Vlachos
7   Medical Center – University of Freiburg, Department of Neuroanatomy, Freiburg im Breisgau, Deutschland
,
U A Wittel
1   Medical Center – University of Freiburg, Department of General and Visceral Surgery, Freiburg im Breisgau, Deutschland
,
D von Elverfeldt
8   Medical Center – University of Freiburg, Division of Medical Physics, Freiburg im Breisgau, Deutschland
,
W Reichardt
8   Medical Center – University of Freiburg, Division of Medical Physics, Freiburg im Breisgau, Deutschland
,
M Boerries
3   Medical Center – University of Freiburg, Institute of Medical Bioinformatics and Systems Medicine, Freiburg im Breisgau, Deutschland
,
G Andrieux
3   Medical Center – University of Freiburg, Institute of Medical Bioinformatics and Systems Medicine, Freiburg im Breisgau, Deutschland
,
G J Heynen
9   Medical Department – Charité Universitätsmedizin Berlin, Division of Hematology, Oncology and Tumor Immunology, Berlin, Deutschland
,
S Fichtner-Feigl
1   Medical Center – University of Freiburg, Department of General and Visceral Surgery, Freiburg im Breisgau, Deutschland
,
L Hannibal
10   Medical Center – University of Freiburg, Department of Pediatrics, Freiburg im Breisgau, Deutschland
,
D A Ruess
1   Medical Center – University of Freiburg, Department of General and Visceral Surgery, Freiburg im Breisgau, Deutschland
› Author Affiliations
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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. While anabolic pathways, glycolysis and autophagy were also affected, mitochondrial alterations persisted longterm into a therapy resistant state.

The resulting vulnerability to induction of ferroptotic cell death via combined SHP2/MEK1/2 and glutathione peroxidase (GPX4) inhibition provides a metabolic lever to reinforce RAS-pathway inhibition for targeted PDAC treatment.



Publication History

Article published online:
04 September 2025

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