Please use this identifier to cite or link to this item: http://dx.doi.org/10.25673/118321
Title: A novel AMPK inhibitor sensitizes pancreatic cancer Cells to ferroptosis induction
Author(s): Schneider, Carolin
Hilbert, Jorina
Genevaux, Franziska
Höfer, Stefanie
Krauß, Lukas
Schicktanz, Felix
Tapia Contreras, ConstanzaLook up in the Integrated Authority File of the German National Library
Jansari, Shaishavi
Papargyriou, Aristeidis
Richter, Thorsten
Alfayomy, Abdallah M.
Falcomatà, ChiaraLook up in the Integrated Authority File of the German National Library
Schneeweis, Christian
Orben, Felix
Öllinger, Ruppert
Wegwitz, Florian
Boshnakovska, Angela
Rehling, Peter
Müller, Denise
Ströbel, PhilippLook up in the Integrated Authority File of the German National Library
Ellenrieder, VolkerLook up in the Integrated Authority File of the German National Library
Conradi, Lena-ChristinLook up in the Integrated Authority File of the German National Library
Hessmann, Elisabeth
Ghadimi, MichaelLook up in the Integrated Authority File of the German National Library
Grade, MarianLook up in the Integrated Authority File of the German National Library
Wirth, Matthias
Steiger, KatjaLook up in the Integrated Authority File of the German National Library
Rad, RolandLook up in the Integrated Authority File of the German National Library
Kuster, Bernhard
Sippl, WolfgangLook up in the Integrated Authority File of the German National Library
Reichert, MaximilianLook up in the Integrated Authority File of the German National Library
Saur, DieterLook up in the Integrated Authority File of the German National Library
Schneider, Günter
Issue Date: 2024
Type: Article
Language: English
Abstract: Cancer cells must develop strategies to adapt to the dynamically changing stresses caused by intrinsic or extrinsic processes, or therapeutic agents. Metabolic adaptability is crucial to mitigate such challenges. Considering metabolism as a central node of adaptability, it is focused on an energy sensor, the AMP-activated protein kinase (AMPK). In a subtype of pancreatic ductal adenocarcinoma (PDAC) elevated AMPK expression and phosphorylation is identified. Using drug repurposing that combined screening experiments and chemoproteomic affinity profiling, it is identified and characterized PF-3758309, initially developed as an inhibitor of PAK4, as an AMPK inhibitor. PF-3758309 shows activity in pre-clinical PDAC models, including primary patient-derived organoids. Genetic loss-of-function experiments showed that AMPK limits the induction of ferroptosis, and consequently, PF-3758309 treatment restores the sensitivity toward ferroptosis inducers. The work established a chemical scaffold for the development of specific AMPK-targeting compounds and deciphered the framework for the development of AMPK inhibitor-based combination therapies tailored for PDAC.
URI: https://opendata.uni-halle.de//handle/1981185920/120280
http://dx.doi.org/10.25673/118321
Open Access: Open access publication
License: (CC BY 4.0) Creative Commons Attribution 4.0(CC BY 4.0) Creative Commons Attribution 4.0
Journal Title: Advanced science
Publisher: Wiley-VCH
Publisher Place: Weinheim
Volume: 11
Issue: 31
Original Publication: 10.1002/advs.202307695
Page Start: 1
Page End: 18
Appears in Collections:Open Access Publikationen der MLU