Abstract
Abstract Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with a devastating prognosis. Gemcitabine, a pyrimidine anti-metabolite, is a cornerstone in PDA therapy, but resistance remains a major hurdle in clinical care. Metabolic reprogramming is an important driver of chemoresistance. Accordingly, targeting these altered metabolic pathways can improve response to treatment. To investigate metabolic vulnerabilities, we generated models of acquired PDA gemcitabine resistance. Screening common metabolic inhibitors we observed that gemcitabine-resistant cells were exquisitely susceptible to statins, inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. This is due to a downregulation of the mevalonate biosynthesis pathway in gemcitabine-resistant cells. Importantly, the statin sensitivity correlates with the extent of the gemcitabine resistance, suggesting this metabolic vulnerability is gradually gained during acquisition of resistance. Rescue experiments showed that statins induce apoptosis by reduced protein geranylation of small GTPases. Finally, we find that pitavastatin inhibits growth of gemcitabine resistant tumors in immune competent models. Collectively, these data suggest that targeting the HMG-CoA reductase is a metabolic vulnerability that is gained in PDA cells upon the acquisition of gemcitabine resistance. The treatment combination of gemcitabine and pitavastatin, two widely used compounds in patients, has potential to translate into an immediate clinical benefit and improve survival in this deadly disease. Citation Format: Sabrina Calderon, Alica K. Beutel, Ethan Nghiem, Rima Singh, Natalie Yousefian, Cecily Anaraki, Kevin Gulay, Dennis Juarez, Alexander Kleger, Thomas Seufferlein, Alexander Muir, Cholsoon Jang, Herve Tiriac, David Fruman, Christopher Halbrook. Repurposing Statins to Target Gemcitabine Resistance in Pancreatic Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C052.
Published Version
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