AMPK inhibitor-based combination therapies in pancreatic ductal adenocarcinoma

by Jorina Hilbert
Doctoral thesis
Date of Examination:2025-03-03
Date of issue:2025-02-14
Advisor:Prof. Dr. Günter Schneider
Referee:Prof. Dr. Günter Schneider
Referee:Dr. Shiv K. Singh
Referee:Prof. Dr. Matthias Dobbelstein
Persistent Address: http://dx.doi.org/10.53846/goediss-11067

 

 

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Abstract

English

Regarding the dismal prognosis of pancreatic ductal adenocarcinoma, this thesis aimed to identify a new therapeutic option by inhibiting the adenosine monophosphate-activated protein kinase (AMPK). Since cancer cells grow uncontrollably and require more nutrients and oxygen relatively to healthy tissue, they are forced to undergo metabolic reprogramming. Thus, intervening in energy homeostasis by targeting the central metabolic regulator AMPK seemed a promising approach for cancer therapy. This project foremost used murine pancreatic cancer cells which are either wildtype or contain a genetic knockout of Prkaa1, the gene encoding for the α-subunit of AMPK. Conducting a drug screen in wildtype and knockout cell lines identified Erastin, a ferroptosis inducing agent, to be more effective in AMPK-deficient compared to AMPK-proficient cell lines. Additionally, Erastin applied together with the potential AMPK inhibitor PF-3758309 was discovered to be a synergistic combination, which was also confirmed in patient-derived cell lines and organoids. Further findings revealed a stronger increase of caspase activity and oxidative stress upon Erastin treatment in conditions of genetically or pharmacologically inhibited AMPK. Notably, the voltage-dependent anion channel 1 (VDAC1), an important regulator of mitochondrial homeostasis in the outer membrane, was a stronger upregulated in AMPK knockouts in comparison to wildtype cell lines upon Erastin treatment, indicating that loss of AMPK leads to some sort of homeostatic dysregulation. This project underlines the crucial role of AMPK in cancer and considers AMPK inhibitor-centred combination therapies to be worth further research to establish this therapeutic approach in a clinical context to treat cancer patients.
Keywords: pancreatic ductal adenocarcinoma; AMPK