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Background <p>Cell free DNA (cfDNA) analysis has a large potential for cancer patient diagnosis. Given the evidence that cfDNA partially preserves chromatin architecture of tumor cells, it potentially allows the detection of tumor responses after therapeutic treatment. This study aimed to detect the responses of abemaciclib, a selective inhibitor of cell cycle regulators CDK4 and CDK6, in metastatic recurrent breast cancer patients through cfDNA analysis.</p> Methods <p>Serum-derived cfDNA was purified from breast cancer patients before and after abemaciclib treatment and from healthy donors. cfDNA concentrations were measured, and sequencing analysis was performed to assess enrichment patterns at open chromatin regions.</p> Results <p>Here we show that cfDNA can be used as a valuable marker to monitor cancer burden and responses to drug treatment. cfDNA concentrations are significantly higher in patients with breast cancer than in healthy individuals and decline following abemaciclib therapy. Sequencing analysis reveals distinct cfDNA signatures between treated and untreated samples, particularly at chromatin regions linked to cell death and pathways regulated by CDK4 and CDK6. Chromatin features also differ between long-term responders and short-term progression cases. Pathway analysis identifies the Polycomb complex as a potential modulator of treatment efficacy, and inhibition of its enzyme EZH2 enhanced the anti-proliferative effect of abemaciclib in luminal breast cancer cells.</p> Conclusion <p>Our findings suggest that cfDNA profiling captures molecular changes induced by targeted therapy and may serve as a practical biomarker for treatment monitoring and prediction of therapeutic response. This research provides insight into the mechanisms of CDK4/6 inhibitor action in metastatic breast cancer.</p>

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Exploring the mechanism of action of abemaciclib in breast cancer through circulating chromatin fragments

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月18日

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  • Mamoru Takada,
  • Sakuntha Gunarathna,
  • Regina Nguyen,
  • Muhan Yu,
  • Paige Bonnet,
  • Hideyuki Yamada,
  • Takeshi Nagashima,
  • Hiroshi Fujimoto,
  • Junta Sakakibara,
  • Hiroto Yamamoto,
  • Mayumi Iida,
  • Tsutomu Kawaguchi,
  • Masayuki Otsuka,
  • Motoki Takaku

摘要

Background

Cell free DNA (cfDNA) analysis has a large potential for cancer patient diagnosis. Given the evidence that cfDNA partially preserves chromatin architecture of tumor cells, it potentially allows the detection of tumor responses after therapeutic treatment. This study aimed to detect the responses of abemaciclib, a selective inhibitor of cell cycle regulators CDK4 and CDK6, in metastatic recurrent breast cancer patients through cfDNA analysis.

Methods

Serum-derived cfDNA was purified from breast cancer patients before and after abemaciclib treatment and from healthy donors. cfDNA concentrations were measured, and sequencing analysis was performed to assess enrichment patterns at open chromatin regions.

Results

Here we show that cfDNA can be used as a valuable marker to monitor cancer burden and responses to drug treatment. cfDNA concentrations are significantly higher in patients with breast cancer than in healthy individuals and decline following abemaciclib therapy. Sequencing analysis reveals distinct cfDNA signatures between treated and untreated samples, particularly at chromatin regions linked to cell death and pathways regulated by CDK4 and CDK6. Chromatin features also differ between long-term responders and short-term progression cases. Pathway analysis identifies the Polycomb complex as a potential modulator of treatment efficacy, and inhibition of its enzyme EZH2 enhanced the anti-proliferative effect of abemaciclib in luminal breast cancer cells.

Conclusion

Our findings suggest that cfDNA profiling captures molecular changes induced by targeted therapy and may serve as a practical biomarker for treatment monitoring and prediction of therapeutic response. This research provides insight into the mechanisms of CDK4/6 inhibitor action in metastatic breast cancer.