ArticlePloS one2019
P16 methylation increases the sensitivity of cancer cells to the CDK4/6 inhibitor palbociclib.
Article in PloS one, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 34 citations in OpenAlex.
- Synthetic lethality in cancer: mechanisms, therapeutic exploitation and clinical translation.Signal transduction and targeted therapy · 2026Review
- Gastric Cancer: Pathobiology and Therapeutics.MedComm · 2026Review
- CDK4/6-targeted therapy for gastrointestinal cancers: from resistance mechanisms to immuno-combination strategies guided by biomarkers.Frontiers in immunology · 2026Review
- The importance of sex dimorphism in liver metabolism and progressive liver diseases.Biology of sex differences · 2025Review
- Development of CDK4/6 Inhibitors in Gastrointestinal Cancers: Biomarkers to Move Forward.Current issues in molecular biology · 2025Review
- TTC7B triggers the PI4KA-AKT1-RXRA-FTO axis and inhibits colon cancer cell proliferation by increasing RNA methylation.International journal of biological sciences · 2025Article
- P16iScience · 2024Article
- Novel strategy for activating gene expression through triplex DNA formation targeting epigenetically suppressed genes.RSC chemical biology · 2024Article
- Pleural mesothelioma (PMe): The evolving molecular knowledge of a rare and aggressive cancer.Molecular oncology · 2024Review
- CDK4/6 inhibitors in lung cancer: current practice and future directions.European respiratory review : an official journal of the European Respiratory Society · 2024Review
- Pancreatic Neuroendocrine Tumors: Signaling Pathways and Epigenetic Regulation.International journal of molecular sciences · 2024Review
- Cytoplasmic Expression of p16 Is Associated with Carcinoma Breast: It Is Not an Artifact.Iranian journal of pathology · 2024Article
- Strategy of combining CDK4/6 inhibitors with other therapies and mechanisms of resistance.International journal of clinical and experimental pathology · 2024Review
- Decreased sensitivity of cyclin-dependent kinase 4/6 inhibitors, palbociclib and abemaciclib to canine lymphoma cells with high p16 protein expression and low retinoblastoma protein phosphorylation.The Journal of veterinary medical science · 2023Article
- CDK6 Degradation Is Counteracted by p16Cancers · 2022Article
- Review
- Methylation and Noncoding RNAs in Gastric Cancer: Everything Is Connected.International journal of molecular sciences · 2021Review
- Sex and Race-Related DNA Methylation Changes in Hepatocellular Carcinoma.International journal of molecular sciences · 2021Review
- Epigenetic Silencing ofIndian journal of clinical biochemistry : IJCB · 2021Article
- Breast Cancer Resistance to Cyclin-Dependent Kinases 4/6 Inhibitors: Intricacy of the Molecular Mechanisms.Frontiers in oncology · 2021Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The P16 (CDKN2Aink4a) gene is an endogenous CDK4/6 inhibitor. Palbociclib (PD0332991) is an anti-CDK4/6 chemical for cancer treatment. P16 is most frequently inactivated by copy number deletion and DNA methylation in cancers. It is well known that cancer cells with P16 deletion are more sensitive to palbociclib than those without. However, whether P16 methylation is related to palbociclib sensitivity is not known. By analyzing public pharmacogenomic datasets, we found that the IC50 of palbociclib in cancer cell lines (n = 522) was positively correlated with both the P16 expression level and P16 gene copy number. Our experimental results further showed that cancer cell lines with P16 methylation were more sensitive to palbociclib than those without. To determine whether P16 methylation directly increased the sensitivity of cancer cells to palbociclib, we induced P16 methylation in the lung cancer cell lines H661 and HCC827 and the gastric cancer cell line BGC823 via an engineered P16-specific DNA methyltransferase (P16-Dnmt) and found that the sensitivity of these cells to palbociclib was significantly increased. The survival rate of P16-Dnmt cells was significantly lower than that of vector control cells 48 hrs post treatment with palbociclib (10 μM). Notably, palbociclib treatment also selectively inhibited the proliferation of the P16-methylated subpopulation of P16-Dnmt cells, further indicating that P16 methylation can increase the sensitivity of cells to this CDK4/6 inhibitor. These results were confirmed in an animal experiment. In conclusion, inactivation of the P16 gene by DNA methylation can increase the sensitivity of cancer cells to palbociclib.
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