Targeting the mevalonate pathway enhances the efficacy of 5-fluorouracil by regulating pyroptosis

• Published in: Medical oncology (Northwood, London, England) London, England), 2024-11, Vol.42 (1), p.9, Article 9
• Main Authors: Xing, Zongrui, Ma, Yong, Jiang, Xiangyan, Qing, Huiguo, Wu, Yuxia, Che, Shengfu, Gao, Zhongti, Wang, Keshen, Wang, Tao, He, Qichen, Li, Zhigang, Zhao, Bin, Liu, Wenbo, Sun, Haonan, Yu, Zeyuan
• Format: Article
• Language: English
• Subjects: Animals; Antimetabolites, Antineoplastic - pharmacology; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Cancer therapies; Cell culture; Cell cycle; Cell Line, Tumor; Chemotherapy; Drug Resistance, Neoplasm - drug effects; Drug Synergism; Enzymes; Female; Fluorouracil - pharmacology; Hematology; Humans; Hydroxymethylglutaryl CoA Reductases - metabolism; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Internal Medicine; Investigations; Male; Medical prognosis; Medicine; Medicine & Public Health; Metabolism; Metabolites; Metastasis; Mevalonic Acid - metabolism; Mice; Normal distribution; Oncology; Original Paper; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pathology; Polyisoprenyl Phosphates - metabolism; Polyisoprenyl Phosphates - pharmacology; Pyroptosis - drug effects; Signal transduction; Simvastatin - pharmacology; Survival analysis
• ISSN: 1559-131X; 1357-0560; 1559-131X
• DOI: 10.1007/s12032-024-02557-5

The 5-fluorouracil (5-FU)-based chemotherapy regimen is a primary strategy for treating pancreatic cancer (PC). However, challenges related to 5-FU resistance persist. Investigating the mechanisms of 5-FU resistance and identifying a clinically viable therapeutic strategy are crucial for improving the prognosis of PC. Here, through clinical samples analysis, we found that the expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme in mevalonate metabolism, is negatively correlated with the efficacy of 5-FU treatment. There is a significant correlation between HMGCR and the pyroptosis marker gasdermin D (GSDMD), and the HMGCR inhibitor simvastatin can significantly inhibit the activation of pyroptosis signaling. The exogenous addition of geranylgeranyl pyrophosphate (GGPP), a key metabolite of the mevalonate pathway, can significantly reduce sensitivity to 5-FU, and simvastatin combined with 5-FU demonstrates a strong synergistic effect. Furthermore, in organoid models and genetically engineered mice with spontaneous PC, the combination of simvastatin and 5-FU significantly inhibits tumor growth. In conclusion, our study reveals the critical role of the mevalonate pathway in 5-FU resistance and proposes a clinically feasible combination therapy strategy.