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mTOR-driven autophagy suppression defines metabolic vulnerability in CDK4/6 inhibitor-resistant HR+/HER2- breast

Luise von Wichert1,2, Alina Stroh1,2, Marie Witt1,2

  • 1Institute of Molecular Oncology, Universities of Gießen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Philipps-University, Marburg, Germany.

Cell Death & Disease
|February 19, 2026
PubMed

Insights

Acquired resistance to CDK4/6 inhibitors in breast cancer (BC) involves mTORC1 hyperactivation and suppressed autophagy. Targeting this metabolic vulnerability with drugs like Metformin offers a new strategy for treating resistant HR+/HER2- BC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Pathways

Background:

  • Hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer (BC) is common.
  • CDK4/6 inhibitors (CDK4/6i) plus endocrine therapy improve outcomes but acquired resistance is a challenge.

Purpose of the Study:

  • Investigate the mechanisms of acquired resistance to CDK4/6i in HR+/HER2- BC.
  • Identify metabolic vulnerabilities in resistant BC cells.
  • Explore potential therapeutic strategies targeting these vulnerabilities.

Main Methods:

  • Utilized HR+/HER2- BC models with acquired resistance to Palbociclib or Ribociclib.
  • Performed gene expression profiling and metabolic assays.
  • Conducted mechanistic studies involving mTORC1, autophagy, and AMPK pathways.
  • Analyzed clinical BC samples using immunohistochemistry.

Main Results:

  • Resistant BC clones exhibited mTORC1 hyperactivation and suppressed autophagy.
  • Gene expression showed enrichment of glycolysis and mTORC1 pathways.
  • Resistant cells were sensitive to metabolic inhibitors Metformin and Dichloroacetate (DCA).
  • mTORC1 overactivation impaired autophagy via ULK1-Ser757 phosphorylation.
  • Metabolic drug treatment induced apoptosis in resistant cells.
  • Clinical samples showed a correlation between high mTORC1 activity and suppressed autophagy.

Conclusions:

  • mTORC1-mediated autophagy defects are a key feature of CDK4/6i-resistant BC.
  • This metabolic vulnerability can be targeted with drugs like Metformin and DCA.
  • mTORC1-mediated autophagy suppression may serve as a biomarker for metabolic vulnerability in resistant BC.

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