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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月25日

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  • Nicole M. Kettner,
  • Tuyen N. Bui,
  • Juliana Navarro-Yepes,
  • Sanaz Ghotbaldini,
  • Bethanie Quintela,
  • Catherine K. Luo,
  • Nghi Lam,
  • Xiayu Rao,
  • Akshara Singareeka Raghavendra,
  • Yan Wang,
  • Nancy Azizian,
  • T. Kris Eckols,
  • Moses Makokha Kasembeli,
  • Kurt Evans,
  • Min Yi,
  • Hannah Wingate,
  • Jing Wang,
  • Aysegul A. Sahin,
  • Funda Meric-Bernstam,
  • Kelly K. Hunt,
  • Senthil Damodaran,
  • David J. Tweardy,
  • Debu Tripathy,
  • Khandan Keyomarsi

摘要

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.