Ruess, D. | bioRxiv Science

bioRxiv2025

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

Background & AimsOncogenic 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. MethodsTo 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. ResultsWe 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. ConclusionsThe 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.

cancer biology↗

bioRxiv2021

Comparison of different head and neck positions and behaviour in ridden elite dressage horses between warm-up and competition

Head and neck position (HNP) has been identified in literature as important influence on wellbeing. It was investigated in ridden elite dressage horses whether there is a relation between the HNP, ethological indicators and the grading in the warm-up area and in the test. 49 starters (83%) of a Grand-Prix Special (CDIO5 *) as part of the CHIO in Aachen 2018 and 2019 were examined. For each horse-rider pair, HNP (angle at vertical (AT), poll angle (PA), neck angel (NA)) used were analysed as well as conflict behavior for 3 minutes each in warm-up area and test. 6571 individual frames were used. The noseline was carried significantly less behind the vertical in test vs. warm-up (5.43 {degrees} {+/-} 4.19 vs. 11.01 {degrees} {+/-} 4.54 behind the vertical; T = 34.0; p < 0.05). The horses showed significantly less conflict behavior in the test vs. warm-up (123 {+/-} 54 vs. 160 {+/-} 75) (T = 76.00; p < 0.01). In the latter, a smaller PA and more defensive behaviour of the horses was observed compared to the test. A correlation between the grading of test and HNP was found (R = 0.38; p < 0.05). The further the noseline was behind the vertical, the higher was the chance of a good rating. The higher riders were ranked in the "FEI world ranking", the higher were their marks in the competition (2018: r = -0.69, p < 0.05; 2019: r = -0.76, p < 0.05). Horses of riders higher in world ranking tended to show more unusual oral behaviour (r = -0.30, p < 0.05), and a noseline stronger behind the vertical (r = - 0.37, p < 0.05) resulting in a smaller NA (r = 0.43, p < 0.05). This are from the point of view of animal welfare problematic results.

animal behavior and cognition↗