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

  • NPJ Precis Oncol. 2025 Jul 25;9(1):260. doi: 10.1038/s41698-025-01041-1.
Nicole M Kettner  1  2 ,  Tuyen N Bui  3 ,  Juliana Navarro-Yepes  3 ,  Sanaz Ghotbaldini  3 ,  Bethanie Quintela  3 ,  Catherine K Luo  3 ,  Nghi Lam  3 ,  Xiayu Rao  4 ,  Akshara Singareeka Raghavendra  5 ,  Yan Wang  3 ,  Nancy Azizian  3 ,  T Kris Eckols  6 ,  Moses Makokha Kasembeli  6 ,  Kurt Evans  7 ,  Min Yi  8 ,  Hannah Wingate  8 ,  Jing Wang  4 ,  Aysegul A Sahin  9 ,  Funda Meric-Bernstam  7 ,  Kelly K Hunt  3  8 ,  Senthil Damodaran  5  7 ,  David J Tweardy  6  10 ,  Debu Tripathy  5 ,  Khandan Keyomarsi  11
Affiliations
  • 1. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. [email protected].
  • 2. Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. [email protected].
  • 3. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 4. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 5. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 6. Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 7. Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 8. Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 9. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 10. Department of Cellular and Molecular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030-3772, USA.
  • 11. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. [email protected].
PMID: 40715551 DOI: 10.1038/s41698-025-01041-1
Abstract

Resistance to CDK4/6 inhibitors (CDK4/6i) is a major challenge in treating hormone receptor-positive, HER2-negative metastatic breast Cancer. This study aimed to identify a biomarker predictive of resistance that could also serve as a therapeutic target. Circulating IL-6 levels in 166 patients significantly increased at progression, making IL-6 a non-invasive biomarker to predict CDK4/6i resistance. Knockdown of IL-6 re-sensitized resistant cells to palbociclib and endocrine therapy, underscoring IL-6's critical role in maintaining resistance. Patient-derived xenograft models from patients who progressed within 3 months versus ≥6 months of palbociclib therapy revealed distinct transcriptomic profiles, with later progressors exhibiting IL-6/STAT3 activation, epithelial-to-mesenchymal transition, and immune evasion signatures. Treatment with TTI-101, a STAT3 Inhibitor, significantly reduced tumor growth and improved survival in these models, providing preclinical validation for targeting the IL-6/STAT3 axis. These findings support using IL-6 to guide personalized treatment and combining STAT3 inhibitors with CDK4/6i as a transformative strategy to overcome resistance.

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