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IL-6 predicts CDK4/6 inhibitor resistance, identifying STAT3 as a target in HR + /HER2-negative metastatic breast

Nicole M Kettner1,2, Tuyen N Bui3, Juliana Navarro-Yepes3

  • 1Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. NMKettner@mdanderson.org.

NPJ Precision Oncology
|July 27, 2025
PubMed

Insights

Interleukin-6 (IL-6) is a biomarker predicting resistance to CDK4/6 inhibitors in metastatic breast cancer. Targeting the IL-6/STAT3 pathway with inhibitors like TTI-101 offers a strategy to overcome this resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are standard treatment for hormone receptor-positive, HER2-negative metastatic breast cancer.
  • Acquired resistance to CDK4/6i limits long-term patient benefit and necessitates novel therapeutic strategies.
  • Identifying predictive biomarkers and therapeutic targets is crucial for overcoming treatment resistance.

Purpose of the Study:

  • To identify a biomarker predicting resistance to CDK4/6 inhibitors in metastatic breast cancer.
  • To investigate the role of Interleukin-6 (IL-6) in mediating CDK4/6i resistance.
  • To evaluate the therapeutic potential of targeting the IL-6/STAT3 axis.

Main Methods:

  • Analysis of circulating IL-6 levels in 166 patients with metastatic breast cancer treated with CDK4/6i.
  • In vitro studies involving IL-6 knockdown in resistant cancer cells.
  • Transcriptomic profiling of patient-derived xenograft models stratified by response duration to palbociclib.
  • Preclinical evaluation of a STAT3 inhibitor (TTI-101) in xenograft models.

Main Results:

  • Elevated circulating IL-6 levels at progression served as a non-invasive biomarker for CDK4/6i resistance.
  • IL-6 knockdown restored sensitivity to palbociclib and endocrine therapy in resistant cells.
  • Distinct transcriptomic profiles were observed between early and late progressors, with later progressors showing IL-6/STAT3 activation, epithelial-to-mesenchymal transition, and immune evasion.
  • STAT3 inhibition with TTI-101 significantly reduced tumor growth and improved survival in preclinical models.

Conclusions:

  • Circulating IL-6 is a predictive biomarker for CDK4/6i resistance in metastatic breast cancer.
  • The IL-6/STAT3 signaling axis plays a critical role in maintaining resistance to CDK4/6i and endocrine therapy.
  • Targeting the IL-6/STAT3 pathway, potentially through combination with existing therapies, represents a promising strategy to overcome resistance and improve patient outcomes.

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