Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity
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Abstract
Inducing senescence in cancer cells is emerging as a new therapeutic strategy. In order to find ways to enhance senescence induction by palbociclib, a CDK4/6 inhibitor approved for treatment of metastatic breast cancer, we performed functional genetic screens in palbociclib-resistant cells. Using this approach, we found that loss of CDK2 results in strong senescence induction in palbociclib-treated cells. Treatment with the CDK2 inhibitor indisulam, which phenocopies genetic CDK2 inactivation, led to sustained senescence induction when combined with palbociclib in various cell lines and lung cancer xenografts. Treating cells with indisulam led to downregulation of cyclin H, which prevented CDK2 activation. Combined treatment with palbociclib and indisulam induced a senescence program and sensitized cells to senolytic therapy. Our data indicate that inhibition of CDK2 through indisulam treatment can enhance senescence induction by CDK4/6 inhibition.
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- Authors
- Pogacar, Z., Johnson, J. L., Krenning, L., De Conti, G., Jochems, F., Lieftink, C., Velds, A., Wardak, L., Groot, K., Schepers, A., Wang, L., Song, J.-Y., van de Ven, M., van Tellingen, O., Medema, R. H., Beijersbergen, R. L., Bernards, R., & Leite de Oliveira, R.
- Affiliations
- The Netherlands Cancer Institute (NL)
- ORCID
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2022-09-06
- Volume
- 17
- Issue
- 9
- Pages
- e0273182
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC9447877
- OpenAlex
- W4294844195
- Cited by
- 13
- References
- 67
- Citations by year
- 2025: 2 · 2024: 5 · 2023: 6
- FWCI
- 1.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- SSRN Electronic Journal (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
- Funders
- ERC H2020
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- indisulam, palbociclib, senescence induction, CDK2 inhibition, CDK4/6 inhibitors, cyclin H, senolytic therapy, drug synergy, palbociclib resistance, lung cancer xenografts, metastatic breast cancer
- MeSH terms
- Humans, Piperazines, Pyridines, Sulfonamides, Cell Line, Tumor, Protein Kinase Inhibitors, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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