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

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

Affiliations

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