ArticleMolecular cancer research : MCR2018
Dual Inhibition of CDK4 and CDK2 via Targeting p27 Tyrosine Phosphorylation Induces a Potent and Durable Response in Breast Cancer Cells.
Article in Molecular cancer research : MCR, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 67 citations in OpenAlex.
- Article
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- Oncogenic properties of wild-type DNA repair gene FANCA in breast cancer.Cell reports · 2025Article
- Underlying Mechanism of Fluoride Inhibits Colonic Gland Cells Proliferation by Inducing an Inflammation Response.Biological trace element research · 2025Article
- Impact of CCND1 amplification on the prognosis of hormone receptor-positive, HER2-negative breast cancer patients-correlation of clinical and pathological markers.Breast cancer research and treatment · 2025Article
- CDK4/6 Inhibitor Resistance in ER+ Breast Cancer.Advances in experimental medicine and biology · 2025Review
- Identification of immune-associated biomarker for predicting lung adenocarcinoma: bioinformatics analysis and experiment verification of PTK6.Discover oncology · 2024Article
- Review
- A review on the role of cyclin dependent kinases in cancers.Cancer cell international · 2022Review
- Cancer cell cycle dystopia: heterogeneity, plasticity, and therapy.Trends in cancer · 2022Review
- LINC00265 Promotes Metastasis and Progression of Hepatocellular Carcinoma by Interacting with E2F1 at The Promoter ofCell journal · 2022Article
- Targeting CDK4/6 for Anticancer Therapy.Biomedicines · 2022Review
- CDK4/6 Inhibitors in Combination Therapies: Better in Company Than Alone: A Mini Review.Frontiers in oncology · 2022Review
- Transcription Regulation and Genome Rewiring Governing Sensitivity and Resistance to FOXM1 Inhibition in Breast Cancer.Cancers · 2021Article
- Polyphyllin I, a lethal partner of Palbociclib, suppresses non-small cell lung cancer through activation of p21/CDK2/Rb pathwayCell cycle (Georgetown, Tex.) · 2021Article
- Identification of genes and pathways leading to metastasis and poor prognosis in melanoma.Aging · 2021Article
- p27Cells · 2021Review
- Functional Determinants of Cell Cycle Plasticity and Sensitivity to CDK4/6 Inhibition.Cancer research · 2021Article
- Nobiletin downregulates the SKP2-p21/p27-CDK2 axis to inhibit tumor progression and shows synergistic effects with palbociclib on renal cell carcinoma.Cancer biology & medicine · 2021Article
Corrections and comments
- Erratum issued
Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Cyclin-dependent kinase 4/6 (CDK4/6)-specific inhibitors, such as palbociclib, have shown clinical efficacy, but primary or secondary resistance has emerged as a problem. To develop more effective therapeutic approaches, investigation is needed into the mechanisms of resistance or adaption. Here, it is demonstrated that CDK2 compensates for loss of CDK4 activity to rescue palbociclib-arrested breast cancer cells, suggesting that inhibition of both kinases is required to achieve durable response. In addition, a novel strategy is described to inhibit tyrosine phosphorylation of p27Kip1 (CDKN1B) and simultaneously inhibit both CDK2 and CDK4. p27Kip1 is a required assembly factor for cyclin-CDK4 complexes, but it must be phosphorylated on residue Y88 to open or activate the complex. The Brk-SH3 peptide, ALT, blocks p27 Y88 phosphorylation, inhibiting CDK4. Nonphosphorylated p27 is no longer a target for ubiquitin-mediated degradation and this stabilized p27 now also inhibits CDK2 activity. Thus, ALT induction inhibits both the kinase that drives proliferation (CDK4) and the kinase that mediates resistance (CDK2), causing a potent and long-lasting cell-cycle arrest. ALT arrests growth of all breast cancer subgroups and synergizes with palbociclib to increase cellular senescence and to cause tumor regression in breast cancer xenograft models. The use of ALT demonstrates that both CDK4 and CDK2 need to be inhibited if long-term efficacy is to be achieved and represents a novel modality to inhibit breast cancer cells.
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