Abstract 4453: Glucagon-like peptide-1 receptor agonists target the HIF1α-PFKFB3 pathway to enhance Lenvatinib efficacy and overcome resistance in hepatocellular carcinoma through the reversal of the Warburg effect

Abstract Background: Glucagon-like peptide-1 receptor agonists (GLP1RAs), originally developed for diabetes and obesity treatment, have recently gained attention for their potential anti-tumor effects. However, the mechanisms underlying these effects remain largely unexplored. Given their emerging role in improving metabolic conditions such as fatty liver disease and liver cirrhosis, we hypothesized that GLP1RAs could also target cancer-specific metabolic pathways, a potential that is yet to be fully understood. Hepatocellular carcinoma (HCC), characterized by metabolic reprogramming, including enhanced glycolysis, consequently contributes to chemotherapy resistance and malignancy. This study evaluates the anti-tumor potential of GLP1RAs in HCC, focusing on their ability to reverse the Warburg effect by inhibiting key glycolytic pathways, thereby improving therapeutic outcomes. Methods: A comprehensive series of experiments was conducted using GLP1RAs and Lenvatinib, including cell proliferation, apoptosis, and glycolysis assays. Genes involved in metabolic pathways were screened using PCR analysis, with key targets identified and validated through Western blotting. Metabolic reprogramming was assessed using Seahorse XF analysis and lactate assays to measure extracellular acidification rate and lactate production. Additionally, the synergistic effects of GLP1RAs and Lenvatinib were evaluated to determine their combined therapeutic potential. Results: The combination of GLP1RAs and Lenvatinib demonstrated synergistic effects, suppressing cell proliferation and enhancing apoptosis in Lenvatinib-resistant cell lines. PCR screening and subsequent validation revealed that Lenvatinib resistance was associated with enhanced glycolysis via the HIF1α-PFKFB3 pathway. GLP1RAs treatment significantly inhibited the HIF1α-PFKFB3 pathway, reducing ECAR and lactate production. By reversing the Warburg effect, GLP1RAs suppressed glycolysis and exerted potent anti-tumor effects. Conclusion: GLP1RAs target the HIF1α-PFKFB3 pathway and significantly enhance the anti-tumor efficacy of Lenvatinib by reversing the Warburg effect in Lenvatinib-resistant HCC cells. These significant findings, which suggest that GLP1 can potentially overcome Lenvatinib resistance and improve therapeutic outcomes in advanced HCC, are a testament to the potential of GLP1RAs in cancer treatment. Citation Format: Takayuki Noma, Yuan Li, Yuma Wada, Katsuki Miyazaki, Yuji Morine, Mitsuo Shimada, Ajay Goel. Glucagon-like peptide-1 receptor agonists target the HIF1α-PFKFB3 pathway to enhance Lenvatinib efficacy and overcome resistance in hepatocellular carcinoma through the reversal of the Warburg effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4453.