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Schneider, C.* ; Hilbert, J.* ; Genevaux, F.* ; Höfer, S.* ; Kraus, L.* ; Schicktanz, F.* ; Contreras, C.T.* ; Jansari, S.* ; Papargyriou, A. ; Richter, T.* ; Alfayomy, A.M.* ; Falcomatà, C.* ; Schneeweis, C.* ; Orben, F.* ; Öllinger, R.* ; Wegwitz, F.* ; Boshnakovska, A.* ; Rehling, P.* ; Müller, D.* ; Ströbel, P.* ; Ellenrieder, V.* ; Conradi, L.* ; Hessmann, E.* ; Ghadimi, M.* ; Grade, M.* ; Wirth, M.* ; Steiger, K.* ; Rad, R.* ; Kuster, B.* ; Sippl, W.* ; Reichert, M.* ; Saur, D.* ; Schneider, G.*

A novel AMPK inhibitor sensitizes pancreatic cancer cells to ferroptosis induction.

Adv. Sci.:e2307695 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Ampk ; Ferroptosis ; Pancreatic Cancer; Activated Protein-kinase; Metastasis; Promotes; Phosphorylation; Pf-3758309; Generation; Resistance; Plasticity; Prediction; Molecules
ISSN (print) / ISBN 2198-3844
e-ISSN 2198-3844
Journal Advanced science
Quellenangaben Volume: , Issue: , Pages: , Article Number: e2307695 Supplement: ,
Publisher Wiley
Publishing Place Weinheim
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Stem Cell Research (ISF)
Grants DKTK (German Cancer Consortium) Strategic Initiative Organoid Platform