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

Lin Zhu1, Jiawen Yang1, Fengmei Li2

  • 1Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.

Drug Design, Development and Therapy
|July 8, 2026
PubMed
Abstract

Insights

Metformin enhances CDK4/6 inhibitor efficacy in HR+/HER2- breast cancer by synergistically inhibiting tumor growth. This combination therapy shows promise for improving treatment outcomes in this patient population.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are first-line treatments for HR+/HER2- breast cancer.
  • Limited efficacy of CDK4/6 inhibitors necessitates novel therapeutic strategies.
  • Metformin, an antidiabetic drug, exhibits potential antitumor properties.

Purpose of the Study:

  • To investigate the synergistic anti-cancer effects of metformin combined with the CDK4/6 inhibitor palbociclib on HR+/HER2- breast cancer.
  • To elucidate the underlying molecular mechanisms of this combination therapy.

Main Methods:

  • In vitro studies using human HR+/HER2- breast cancer cell lines.
  • In vivo studies using transplanted tumor mouse models.
  • Analysis of cell proliferation, migration, apoptosis, and key signaling pathways (PI3K/AKT/mTOR).

Main Results:

  • Metformin and palbociclib synergistically inhibited cancer cell proliferation and migration while promoting apoptosis.
  • The combination therapy suppressed the PI3K/AKT/mTOR pathway.
  • Metformin downregulated CDK4, leading to enhanced inhibition of Cyclin D1, E2F, and Rb phosphorylation.
  • Combined treatment synergistically suppressed tumor growth in vivo.

Conclusions:

  • Metformin acts synergistically with CDK4/6 inhibitors like palbociclib in HR+/HER2- breast cancer.
  • This combination therapy presents a promising strategy to enhance treatment efficacy.
  • Metformin may serve as an effective adjunctive therapy for HR+/HER2- breast cancer.
Keywords:
CDK4/6 inhibitorHR+/HER2- breast cancerPI3K/AKT/mTOR pathwaymetforminpalbociclib

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