Crucially, we demonstrated that ER+/HER2+ and ER+/HER2− breast cancer cells rely on aerobic glycolysis differently when mimicking a sensitive or a resistant clinical scenario, hence targeting glucose metabolism can re-sensitize ER+/HER2+ PDR cells to palbociclib and significantly enhance its anti-tumoral effects in ER+/HER2− sensitive cells. Here, ERBB2 is linked to breast cancer.