Cell cycle plasticity underlies fractional resistance to palbociclib in ER+/HER2-breast tumor cells

• 成果类型: Article
• 署名作者: Zikry, Tarek M.; Wolff, Samuel C.; Ranek, Jolene S.; Davis, Harris M.; Naugle, Ander; Luthra, Namit; Whitman, Austin A.; Kedziora, Katarzyna M.; Stallaert, Wayne; Kosorok, Michael R.; Spanheimer, Philip M.; Purvis, Jeremy E.
• 署名单位: University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of North Carolina; University of North Carolina Chapel Hill
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14466
• DOI: 10.1073/pnas.2309261121
• 发表日期: 2024-02-06
• 关键词: 4/6 inhibitor palbociclib; proliferation; letrozole; ki67; e2f; transcription; chemotherapy; quiescence; mechanisms; DECISION

摘要

The CDK4/6 inhibitor palbociclib blocks cell cycle progression in Estrogen receptor- positive, human epidermal growth factor 2 receptor-negative (ER+/HER2-) breast tumor cells. Despite the drug's success in improving patient outcomes, a small percentage of tumor cells continues to divide in the presence of palbociclib-a phenomenon we refer to as fractional resistance. It is critical to understand the cellular mechanisms underlying fractional resistance because the precise percentage of resistant cells in patient tissue is a strong predictor of clinical outcomes. Here, we hypothesize that fractional resistance arises from cell - to - cell differences in core cell cycle regulators that allow a subset of cells to escape CDK4/6 inhibitor therapy. We used multiplex, single - cell imaging to identify fractionally resistant cells in both cultured and primary breast tumor samples resected from patients. Resistant cells showed premature accumulation of multiple G1 regulators including E2F1, retinoblastoma protein, and CDK2, as well as enhanced sensitivity to pharmacological inhibition of CDK2 activity. Using trajectory inference approaches, we show how plasticity among cell cycle regulators gives rise to alternate cell cycle paths that allow individual tumor cells to escape palbociclib treatment. Understanding drivers of cell cycle plasticity, and how to eliminate resistant cell cycle paths, could lead to improved cancer therapies targeting fractionally resistant cells to improve patient outcomes.