@article{41cd7248cdb442c69f62b36b1b4a81a1,
title = "Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity",
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.",
author = "Ziva Pogacar and Johnson, {Jackie L.} and Lenno Krenning and {de Conti}, Giulia and Fleur Jochems and Cor Lieftink and Arno Velds and Leyma Wardak and Kelvin Groot and Arnout Schepers and Liqin Wang and Ji-Ying Song and {van de Ven}, Marieke and {van Tellingen}, Olaf and Medema, {Rene H.} and Beijersbergen, {Roderick L.} and Rene Bernards and {Leite de Oliveira}, Rodrigo",
note = "Funding Information: EC | H2020 | H2020 Priority Excellent Science | H2020 European Research Council (ERC):Ziva Pogacar,Jackie L. Johnson,Giulia De Conti,Cor Lieftink,Leyma Wardak,Fleur Jochems, Kelvin Groot,Arnout Schepers,Liqin Wang,Roderick Beijersbergen,Rene R Bernards,Rodrigo Leite de Oliveira 787925 Other authors worked without finding. We would like to thank Artur Burylo, Natalie Proost, Jordi van Iersel and Marcio Sousa for help with experiments and Katrien Berns for critical discussion on screening techniques. We also thank the NKI Bioimaging facility, Genomics core facility and pre-Clinical Intervention Unit for their technical support. Publisher Copyright: {\textcopyright} 2022 Pogacar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
year = "2022",
month = sep,
doi = "https://doi.org/10.1371/journal.pone.0273182",
language = "English",
volume = "17",
pages = "e0273182",
journal = "PLOS ONE",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "9 September",
}