GLP-1RA targets `AMPKα1-HIF1α-PFKFB3` axis, enhancing Lenvatinib response in liver cancer

Hepatocellular carcinoma (HCC), a prevalent and aggressive liver cancer, is notoriously challenging to treat, often developing resistance to targeted therapies like Lenvatinib. A key driver of this resistance is metabolic reprogramming, particularly enhanced glycolysis, which fuels cancer cell proliferation and survival. Current treatments struggle to overcome this metabolic adaptation, leaving a critical gap for novel therapeutic strategies. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely recognized for their metabolic benefits in diabetes and obesity, are now being explored for their potential anti-tumor effects, with a focus on their ability to modulate cancer-specific metabolic vulnerabilities.

Researchers investigated the anti-tumor effects of a GLP-1RA in Lenvatinib-resistant HCC cell models, focusing on its impact on glycolytic pathways and its ability to enhance sensitivity to Lenvatinib. They characterized the metabolic profile of resistant HCC cells, observing changes in key metabolic regulators. The study then evaluated the effects of GLP-1RA treatment, both alone and in combination with Lenvatinib, on these cells. The primary endpoints included assessing AMPKα1 activity, HIF-1α and PFKFB3 expression, glycolytic activity, and apoptosis rates, as well as overall tumor cell growth inhibition.

Lenvatinib-resistant HCC cells exhibited a distinct metabolic signature characterized by suppressed AMPKα1 activity, coupled with increased expression of HIF-1α and PFKFB3, which collectively promoted a highly glycolytic adaptation. Treatment with a GLP-1RA effectively reversed these metabolic alterations. It restored AMPKα1 activity while simultaneously suppressing the HIF-1α/PFKFB3 signaling axis, leading to a significant reduction in glycolytic activity. This metabolic shift was accompanied by an enhancement in apoptosis, indicating a direct anti-cancer effect. Crucially, the combination of GLP-1RA and Lenvatinib demonstrated synergistic efficacy. > Combination treatment with GLP-1RA and Lenvatinib significantly inhibited tumor cell growth in resistant models, suggesting that targeting the AMPKα1/HIF-1α/PFKFB3 axis overcomes a key metabolic vulnerability in Lenvatinib-resistant HCC.