IL-6 predicts CDK4/6 inhibitor resistance, identifying STAT3 as a target in HR + /HER2-negative metastatic breast cancer
Nicole M. Kettner, Tuyen Bui, Juliana Navarro-Yepes, Sanaz Ghotbaldini, Bethanie Quintela, Catherine K. Luo, Nghi Lam, Xiayu Rao, Akshara Singareeka Raghavendra, Yan Wang, Nancy G. Azizian, T. Kris Eckols, Moses M. Kasembeli, Kurt W. Evans, Min Yi, Hannah F. Wingate, Jing Wang, Ayşegül A. Şahin, Funda Meric‐Bernstam, Kelly K. Hunt, Senthil Damodaran, David J. Tweardy, Debu Tripathy, Khandan Keyomarsi
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.