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.