Advanced Science (Aug 2024)

A Novel AMPK Inhibitor Sensitizes Pancreatic Cancer Cells to Ferroptosis Induction

  • Carolin Schneider,
  • Jorina Hilbert,
  • Franziska Genevaux,
  • Stefanie Höfer,
  • Lukas Krauß,
  • Felix Schicktanz,
  • Constanza Tapia Contreras,
  • Shaishavi Jansari,
  • Aristeidis Papargyriou,
  • Thorsten Richter,
  • Abdallah M. Alfayomy,
  • Chiara Falcomatà,
  • Christian Schneeweis,
  • Felix Orben,
  • Ruppert Öllinger,
  • Florian Wegwitz,
  • Angela Boshnakovska,
  • Peter Rehling,
  • Denise Müller,
  • Philipp Ströbel,
  • Volker Ellenrieder,
  • Lena Conradi,
  • Elisabeth Hessmann,
  • Michael Ghadimi,
  • Marian Grade,
  • Matthias Wirth,
  • Katja Steiger,
  • Roland Rad,
  • Bernhard Kuster,
  • Wolfgang Sippl,
  • Maximilian Reichert,
  • Dieter Saur,
  • Günter Schneider

DOI
https://doi.org/10.1002/advs.202307695
Journal volume & issue
Vol. 11, no. 31
pp. n/a – n/a

Abstract

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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.

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