Researchers at Philipps-Universität Marburg have identified a metabolic vulnerability in therapy-resistant forms of hormone receptor-positive, HER2-negative breast cancer. In experimental models, they showed that tumor cells become particularly susceptible to interventions in energy metabolism after the development of resistance to CDK4/6 inhibitors – the standard therapy in the advanced stage. Drugs such as metformin or dichloroacetate can put these cells under massive energy stress and lead to programmed cell death. The results were published on March 4, 2026 in the journal “Cell Death & Disease”.

About 70 percent of all breast cancers belong to this subtype. CDK4/6 inhibitors are now routinely used in the first-line treatment of metastatic hormone receptor-positive breast cancer. However, after an initial response, many tumors develop resistance, worsening the prognosis and limiting further treatment options.

The Marburg team led by Luise von Wichert and Dr. Niklas Gremke systematically characterized resistant cell clones. This revealed a characteristic phenotype: overactivation of the mTOR signaling pathway, inhibition of autophagy – the cellular recycling mechanism – and a strong dependence on mitochondrial energy metabolism. The blocked autophagy prevents the cells from being able to fall back on their own reserves in the event of a lack of energy. If metabolic stress is also triggered – for example by metformin, which inhibits mitochondrial respiration – the resistant cells die through programmed cell death.

Resistance is not only a therapeutic failure, but can open up new targets, explained Dr. Niklas Gremke, junior research group leader and clinician scientist. The study defines a biologically clearly definable resistance subtype that could enable targeted follow-up therapies.

In the long term, metabolic characterization of resistant tumors could help to better stratify patients after failure of CDK4/6 therapy. Women with this resistance profile could benefit from an additional treatment that specifically disrupts the energy metabolism of the cancer cells. In this way, the work contributes to more personalized breast cancer medicine, in which treatment decisions are increasingly based on the individual molecular and metabolic properties of the tumor.

The results were obtained as part of Luise von Wichert’s medical doctorate at the Institute of Molecular Oncology at the Philipps University of Marburg. Dr. Niklas Gremke supervised the work as a Clinician Scientist in the SUCCESS program of the University of Marburg and the University Hospital Marburg as well as the University Center for Tumor Diseases (UCT) Frankfurt-Marburg. The study was supported by the von Behring-Röntgen Foundation and UKGM research funding, among others.

Original Paper:

mTOR-driven autophagy suppression defines metabolic vulnerability in CDK4/6 inhibitor-resistant HR+/HER2− breast cancer | Cell Death & Disease

Editor: X-Press Journalistenbüro GbR

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