Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity

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 th...

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Veröffentlicht in:PloS one Jg. 17; H. 9; S. e0273182
Hauptverfasser: Pogacar, Ziva, Johnson, Jackie L., Krenning, Lenno, De Conti, Giulia, Jochems, Fleur, Lieftink, Cor, Velds, Arno, Wardak, Leyma, Groot, Kelvin, Schepers, Arnout, Wang, Liqin, Song, Ji-Ying, van de Ven, Marieke, van Tellingen, Olaf, Medema, Rene H., Beijersbergen, Roderick L., Bernards, Rene, Leite de Oliveira, Rodrigo
Format: Journal Article
Sprache:Englisch
Veröffentlicht: San Francisco Public Library of Science 06.09.2022
Public Library of Science (PLoS)
Schlagworte:
Analysis
Breast cancer
Cancer
Cancer therapies
Care and treatment
Cell cycle
Clinical trials
Colorectal cancer
Combined treatment
Cyclin-dependent kinase 2
Cyclin-dependent kinase 4
Experiments
Gene expression
Genetic screening
Inactivation
Kinases
Lung cancer
Lung diseases
Medicine and Health Sciences
Metastases
Morphology
Research and Analysis Methods
Senescence
Tumor cell lines
Xenografts
Xenotransplantation
Netherlands
ISSN:1932-6203, 1932-6203
Online-Zugang:Volltext
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Zusammenfassung: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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Competing Interests: R.B is the founder of the company Oncosence (https://www.oncosence.com), which aims to develop senescence-inducing and senolytic compounds to treat cancer. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Current Address: CRISPR Expertise Center, Cancer Center Amsterdam, Amsterdam University Medical Center, Amsterdam, The Netherlands
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0273182