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PreprintCited by 13Telomeres, Telomerase, and SenescenceAdvanced Breast Cancer TherapiesCancer-related Molecular Pathways

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

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Pogacar, Ziva, Johnson, Jackie L., Krenning, Lenno, De Conti, Giulia, Lieftink, Cor, Velds, Arno, Wardak, Leyma, Jochems, Fleur, Groot, Kelvin, Schepers, Arnout, Wang, Liqin, Song, Ji-Ying, van de Ven, Marieke, van Tellingen, Olaf, Medema, Rene H., Beijersbergen, Roderick L., Bernards, Rene, de Oliveira, Rodrigo Leite·2021·PLoS ONE
DOI 10.1101/2021.10.18.464788PMC PMC9447877

Preprint — published as 10.1371/journal.pone.0273182 · Paper page

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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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Metadata

Authors
Pogacar, Z., Johnson, J. L., Krenning, L., De Conti, G., Lieftink, C., Velds, A., Wardak, L., Jochems, F., Groot, K., Schepers, A., Wang, L., Song, J.-Y., van de Ven, M., van Tellingen, O., Medema, R. H., Beijersbergen, R. L., Bernards, R., & de Oliveira, R. L.
Affiliations
The Netherlands Cancer Institute (NL)
Corresponding author
de Oliveira, Rodrigo Leite
ORCID
Venue
PLoS ONE
Publisher
openRxiv
Published
2021-10-19
Volume
17
Issue
9
Pages
e0273182-e0273182
ISSN
1932-6203 (ISSN-L)
DOI
10.1101/2021.10.18.464788
PMC
PMC9447877
OpenAlex
W4294844195
Cited by
13
References
2
Citations by year
2025: 2 · 2024: 5 · 2023: 6
FWCI
1.73
Type
journal article
Language
en
Open access
Licence
cc-by
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
  • KWF Kankerbestrijding
  • Oncode Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
  • Health Sciences › Medicine › Oncology › 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

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