TY - JOUR
T1 - A Novel AMPK Inhibitor Sensitizes Pancreatic Cancer Cells to Ferroptosis Induction
AU - Schneider, Carolin
AU - Hilbert, Jorina
AU - Genevaux, Franziska
AU - Höfer, Stefanie
AU - Krauß, Lukas
AU - Schicktanz, Felix
AU - Contreras, Constanza Tapia
AU - Jansari, Shaishavi
AU - Papargyriou, Aristeidis
AU - Richter, Thorsten
AU - Alfayomy, Abdallah M.
AU - Falcomatà, Chiara
AU - Schneeweis, Christian
AU - Orben, Felix
AU - Öllinger, Ruppert
AU - Wegwitz, Florian
AU - Boshnakovska, Angela
AU - Rehling, Peter
AU - Müller, Denise
AU - Ströbel, Philipp
AU - Ellenrieder, Volker
AU - Conradi, Lena
AU - Hessmann, Elisabeth
AU - Ghadimi, Michael
AU - Grade, Marian
AU - Wirth, Matthias
AU - Steiger, Katja
AU - Rad, Roland
AU - Kuster, Bernhard
AU - Sippl, Wolfgang
AU - Reichert, Maximilian
AU - Saur, Dieter
AU - Schneider, Günter
N1 - Publisher Copyright:
© 2024 The Author(s). Advanced Science published by Wiley-VCH GmbH.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - AMPK
KW - ferroptosis
KW - pancreatic cancer
UR - http://www.scopus.com/inward/record.url?scp=85196194745&partnerID=8YFLogxK
U2 - 10.1002/advs.202307695
DO - 10.1002/advs.202307695
M3 - Article
AN - SCOPUS:85196194745
SN - 2198-3844
JO - Advanced Science
JF - Advanced Science
ER -