Pharmacologic inhibition of PFKFB3 imposed additional constrains on glucose utilization and significantly enhanced the antitumor efficacy of CDK4/6 inhibition in PDX models.<h4>Conclusions</h4>CDK4/6 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. The gene discussed is PFKFB3; the disease is breast carcinoma.