ArticleProceedings of the National Academy of Sciences of the United States of America2024
Cell cycle plasticity underlies fractional resistance to palbociclib in ER+/HER2- breast tumor cells.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 17 citations in OpenAlex.
- Transcriptional Heterogeneity in Dedifferentiated Liposarcoma Reveals Distinct Cell-Cycle Subtypes.Annals of surgical oncology · 2026Article
- Article
- Targeting casein kinase 1α-mediated FADD phosphorylation restores sensitivity in select CDK4/6 inhibitor-resistant breast cancer models.The Journal of clinical investigation · 2026Article
- Non-Genetic Mechanisms of Fractional Resistance to Abemaciclib in Dedifferentiated Liposarcoma.bioRxiv : the preprint server for biology · 2026Article
- Mathematical analysis of G1/S sub-networks in hematopoietic proliferation: Sequential and lineage-specific activation.iScience · 2026Article
- Distinct p21 dynamics drive alternative routes to whole-genome duplication through a common CDK4/6-dependent polyploid G0 state.bioRxiv : the preprint server for biology · 2026Article
- Glutaminase as a metabolic target of choice to counter acquired resistance to Palbociclib by colorectal cancer cells.Oncogene · 2025Article
- Spherical Manifolds Capture Drug-Induced Changes in Tumor Cell Cycle Behavior.Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing · 2025Article
- Cell Cycle Plasticity and Heterogeneity: An Underappreciated Feature of Cancer and Treatment Response.Cancer heterogeneity and plasticity · 2025Article
- Dual targeting of conserved cell cycle and transcription programs in advanced colorectal cancer by fadraciclib.Evolution, medicine, and public health · 2025Article
- APC/C prevents a noncanonical order of cyclin/CDK activity to maintain CDK4/6 inhibitor-induced arrest.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- DELVE: feature selection for preserving biological trajectories in single-cell data.Nature communications · 2024Article
- Cell cycle plasticity underlies fractional resistance to palbociclib in ER+/HER2- breast tumor cells.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- APC/C prevents non-canonical order of cyclin/CDK activity to maintain CDK4/6 inhibitor-induced arrest.bioRxiv : the preprint server for biology · 2023Article
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
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.
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