Metformin Sensitizes HR+/HER2- Breast Cancer Cells to CDK4/6 Inhibitor via Suppressing of PI3K/AKT/mTOR Signaling Pathway

PURPOSE: CDK4/6 (Cyclin-dependent kinase 4/6) inhibitors are recommended as the first-line treatment for Hormone receptor-positive/human epidermal growth receptor 2-negative (HR+/HER2-) breast cancer, but their efficacy is limited. Metformin, a widely used antidiabetic drug, has demonstrated antitumor potential and can enhance the efficacy of various cancer therapies. Nevertheless, its specific role in sensitizing HR+/HER2- breast cancer to CDK4/6 inhibition and the underlying mechanisms remain poorly defined. METHODS: In this study, the combined anti-HR+/HER2- breast cancer effects of metformin with CDK4/6 inhibitor palbociclib and its potential mechanisms were investigated using human HR+/HER2- breast cancer cell lines in vitro and transplanted tumor mouse models in vivo. RESULTS: Our study demonstrated that the combination of metformin and palbociclib synergistically inhibited proliferation and migration, and promoted apoptosis in HR+/HER2- breast cancer cells. This synergistic anticancer effect was linked to suppression of the PI3K/AKT/mTOR pathway. Mechanistically, metformin downregulated CDK4 protein expression, and its combination with palbociclib led to a more profound suppression of Cyclin D1 and E2F, along with enhanced inhibition of Rb phosphorylation. Moreover, the metformin-palbociclib combination synergistically suppressed tumor growth in vivo. CONCLUSION: Our findings highlighted that metformin could serve as an adjunctive therapy alongside CDK4/6 inhibitors, offering a promising synergistic treatment strategy for HR+/HER2- breast cancer.