ArticleCell cycle (Georgetown, Tex.)2021
Sustained mTORC1 activity during palbociclib-induced growth arrest triggers senescence in ER+ breast cancer cells.
Article in Cell cycle (Georgetown, Tex.), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 40 citations in OpenAlex.
- Small molecule activators of the mitochondrial protease ClpP induce senescence in triple-negative breast cancer cells and sensitize cells to the Bcl-2 inhibitor venetoclax.Cell death & disease · 2026Article
- Review
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- Differential Preclinical Efficacy of Combined CDK4/6 and MEK Inhibition in Low-Grade Serous Ovarian Carcinoma Based onInternational journal of molecular sciences · 2026Article
- Non-Canonical Senescence Phenotype in Resistance to CDK4/6 Inhibitors in ER-Positive Breast Cancer.Biomolecules · 2026Article
- Emerging Targeted and Multimodal Therapeutic Strategies in Breast Cancer: A Comprehensive Review.Breast cancer (Dove Medical Press) · 2026Review
- Alternate actions of CDK4/6 inhibitors beyond cell cycle blockade: unexplored roles in therapy resistance.Cancer metastasis reviews · 2025Review
- Small Molecule Activators of the Mitochondrial Protease ClpP Induce Senescence in Triple-Negative Breast Cancer Cells and Sensitize Cells to the Bcl-2 Inhibitor Venetoclax.Research square · 2025Article
- Nuclear morphometrics coupled with machine learning identifies dynamic states of senescence across age.Nature communications · 2025Article
- TFAP2C-DDR1 axis regulates resistance to CDK4/6 inhibitor in breast cancer.Cancer letters · 2025Article
- Cellular senescence in colorectal cancer: its occurrence, effect and therapy.Frontiers in oncology · 2025Review
- The p21CIP1-CDK4-DREAM axis is a master regulator of genotoxic stress-induced cellular senescence.Nucleic acids research · 2024Article
- Article
- Neutrophil-activating secretome characterizes palbociclib-induced senescence of breast cancer cells.Cancer immunology, immunotherapy : CII · 2024Article
- Autophagy and senescence facilitate the development of antiestrogen resistance in ER positive breast cancer.Frontiers in endocrinology · 2024Review
- Trametinib boosts palbociclib's efficacy in breast cancer via autophagy inhibition.Oncology research · 2024Article
- Genome homeostasis defects drive enlarged cells into senescence.Molecular cell · 2023Article
- Article
- The role of TSC2 in breast cancer: a literature review.Frontiers in oncology · 2023Review
- CDK4/6 inhibitor resistance in estrogen receptor positive breast cancer, a 2023 perspective.Frontiers in cell and developmental biology · 2023Review
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Palbociclib, a selective CDK4/6 kinase inhibitor, is approved in combination with endocrine therapies for the treatment of advanced estrogen receptor positive (ER+) breast cancer. In pre-clinical cancer models, CDK4/6 inhibitors act primarily as cytostatic agents. In two commonly studied ER+ breast cancer cell lines (MCF7 and T47D), CDK4/6 inhibition drives G1-phase arrest and the acquisition of a senescent-like phenotype, both of which are reversible upon palbociclib withdrawal (incomplete senescence). Here we identify an ER+ breast cancer cell line, CAMA1, in which palbociclib treatment induces irreversible cell cycle arrest and senescence (complete senescence). In stark contrast to T47D and MCF7 cells, mTORC1 activity is not stably suppressed in CAMA1 cells during palbociclib treatment. Importantly, inhibition of mTORC1 signaling either by the mTORC1 inhibitor rapamycin or by knockdown of Raptor, a unique component of mTORC1, during palbociclib treatment of CAMA1 cells blocks the induction of complete senescence. These results indicate that sustained mTORC1 activity promotes complete senescence in ER+ breast cancer cells during CDK4/6 inhibitor-induced cell cycle arrest. Consistent with this mechanism, genetic depletion of TSC2, a negative regulator of mTORC1, in MCF7 cells resulted in sustained mTORC1 activity during palbociclib treatment and evoked a complete senescence response. These findings demonstrate that persistent mTORC1 signaling during palbociclib-induced G1 arrest is a potential liability for ER+ breast cancer cells, and suggest a strategy for novel drug combinations with palbociclib.
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