Targeting PFKFB3 to enhance CDK4/6 inhibitor response in ER+ breast cancer.

backgroundCyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are widely used in the treatment of estrogen receptor-positive (ER⁺) breast cancer; however, the metabolic adaptations induced by CDK4/6 inhibition remain incompletely defined. In ER⁺ breast cancer, estrogen signaling plays a central role in coordinating cell cycle progression and metabolic programs that support tumor growth. Glycolytic flux is regulated at the level of phosphofructokinase-1 (PFK1) through the inducible enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), which is transcriptionally regulated by estrogen receptor signaling and has been shown to promote glycolysis and proliferation in ER⁺ breast cancer cells. Yet, how CDK4/6 inhibition intersects with estrogen-regulated glycolytic control to rewire glucose utilization in ER⁺ breast cancer has not been explored.

methodsGlucose metabolism was assessed using extracellular flux analysis, untargeted metabolomics, and stable isotope tracing with uniformly labeled

resultsCDK4/6 inhibition increased glycolytic flux, as evidenced by elevated basal and compensatory glycolysis, accumulation of early glycolytic intermediates, and increased

conclusionsCDK4/6 inhibition rewires glucose metabolism in ER+ breast cancer by increasing glycolytic flux while limiting downstream glucose utilization, resulting in heightened reliance on regulated glycolytic control to maintain metabolic homeostasis during cell cycle arrest. Disruption of this adaptive metabolic state through PFKFB3 inhibition enhances the antitumor effects of CDK4/6 inhibition and supports the therapeutic potential of targeting glycolytic regulation in combination with CDK4/6 inhibitor-directed therapies.