ArticleCell cycle (Georgetown, Tex.)2014
The CDK4/CDK6 inhibitor PD0332991 paradoxically stabilizes activated cyclin D3-CDK4/6 complexes.
Article in Cell cycle (Georgetown, Tex.), 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 43 citations in OpenAlex.
- Advances in Cutaneous Melanoma Therapy: The Emerging Role of CDK4/6 Inhibitors.Pharmacological research · 2025Review
- Preclinical evaluation of CDK4 phosphorylation predicts high sensitivity of pleural mesotheliomas to CDK4/6 inhibition.Molecular oncology · 2024Article
- CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon RB function in malignant peripheral nerve sheath tumors.Science advances · 2023Article
- The Role of Cyclin-Dependent Kinases (CDK) 4/6 in the Ovarian Tissue and the Possible Effects of Their Exogenous Inhibition.Cancers · 2023Review
- CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon restoration of RB function in malignant peripheral nerve sheath tumors.bioRxiv : the preprint server for biology · 2023Article
- CDK4 phosphorylation status and rational use for combining CDK4/6 and BRAF/MEK inhibition in advanced thyroid carcinomas.Frontiers in endocrinology · 2023Article
- Cyclin-dependent Kinase 4/6 Inhibitor Palbociclib in Combination with Ralaniten Analogs for the Treatment of Androgen Receptor-positive Prostate and Breast Cancers.Molecular cancer therapeutics · 2022Article
- CDK4 and CDK6 kinases: From basic science to cancer therapy.Science (New York, N.Y.) · 2022Review
- CCND3 is indispensable for the maintenance of B-cell acute lymphoblastic leukemia.Oncogenesis · 2022Article
- FAM117A Is a New Prognostic Marker of Lung Adenocarcinoma and Predicts Sensitivity to PD0332991.Evidence-based complementary and alternative medicine : eCAM · 2022Article
- Monoclonal antibodies to activated CDK4: use to investigate normal and cancerous cell cycle regulation and involvement of phosphorylations of p21 and p27.Cell cycle (Georgetown, Tex.) · 2022Article
- The folate antagonist methotrexate diminishes replication of the coronavirus SARS-CoV-2 and enhances the antiviral efficacy of remdesivir in cell culture models.Virus research · 2021Article
- CDK4/6 inhibition presents as a therapeutic option for paediatric and adult germ cell tumours and induces cell cycle arrest and apoptosis via canonical and non-canonical mechanisms.British journal of cancer · 2020Article
- Hsa_circ_0079662 induces the resistance mechanism of the chemotherapy drug oxaliplatin through the TNF-α pathway in human colon cancer.Journal of cellular and molecular medicine · 2020Article
- Wogonin Induces Apoptosis and Reverses Sunitinib Resistance of Renal Cell Carcinoma CellsFrontiers in pharmacology · 2020Article
- Cyclin-dependent Kinase 18 Promotes Oligodendrocyte Precursor Cell Differentiation through Activating the Extracellular Signal-Regulated Kinase Signaling Pathway.Neuroscience bulletin · 2019Article
- Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo.Scientific reports · 2019Article
- G1/S cell cycle regulators mediate effects of circadian dysregulation on tumor growth and provide targets for timed anticancer treatment.PLoS biology · 2019Article
- Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer.Nature communications · 2019Article
- Advanced oxidation protein products induce S-phase arrest of hepatocytes via the ROS-dependent, β-catenin-CDK2-mediated pathway.Redox biology · 2018Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
CDK4 and CDK6 bound to D-type cyclins are master integrators of G1 phase cell cycle regulations by initiating the inactivating phosphorylation of the central oncosuppressor pRb. Because of their frequent deregulation in cancer, cyclin D-CDK4/6 complexes are emerging as especially promising therapeutic targets. The specific CDK4/6 inhibitor PD0332991 is currently tested in a growing number of phase II/III clinical trials against a variety of pRb-proficient chemotherapy-resistant cancers. We have previously shown that PD0332991 inhibits not only CDK4/6 activity but also the activation by phosphorylation of the bulk of cyclin D-CDK4 complexes stabilized by p21 binding. Here we show that PD0332991 has either a positive or a negative impact on the activation of cyclin D-CDK4/6 complexes, depending on their binding to p21. Indeed, whereas PD0332991 inhibits the phosphorylation and activity of p21-bound CDK4/6, it specifically stabilized activated cyclin D3-CDK4/6 complexes devoid of p21 and p27. After elimination of PD0332991, these activated cyclin D3-CDK4/6 complexes persisted for at least 24 h, resulting in paradoxical cell cycle entry in the absence of a mitogenic stimulation. This unsuspected positive effect of PD0332991 on cyclin D3-CDK4/6 activation should be carefully assessed in the clinical evaluation of PD0332991, which until now only involves discontinuous administration protocols.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.