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...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2022-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0273182 |
| _version_ | 1818023014790332416 |
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| author | Ziva Pogacar Jackie L Johnson Lenno Krenning Giulia De Conti Fleur Jochems Cor Lieftink Arno Velds Leyma Wardak Kelvin Groot Arnout Schepers Liqin Wang Ji-Ying Song Marieke van de Ven Olaf van Tellingen Rene H Medema Roderick L Beijersbergen Rene Bernards Rodrigo Leite de Oliveira |
| author_facet | Ziva Pogacar Jackie L Johnson Lenno Krenning Giulia De Conti Fleur Jochems Cor Lieftink Arno Velds Leyma Wardak Kelvin Groot Arnout Schepers Liqin Wang Ji-Ying Song Marieke van de Ven Olaf van Tellingen Rene H Medema Roderick L Beijersbergen Rene Bernards Rodrigo Leite de Oliveira |
| author_sort | Ziva Pogacar |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T03:37:35Z |
| format | Article |
| id | doaj.art-6f29ef7b9b734b128186d1949fb65c09 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T03:37:35Z |
| publishDate | 2022-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-6f29ef7b9b734b128186d1949fb65c092022-12-22T02:03:40ZengPublic Library of Science (PLoS)PLoS ONE1932-62032022-01-01179e027318210.1371/journal.pone.0273182Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity.Ziva PogacarJackie L JohnsonLenno KrenningGiulia De ContiFleur JochemsCor LieftinkArno VeldsLeyma WardakKelvin GrootArnout SchepersLiqin WangJi-Ying SongMarieke van de VenOlaf van TellingenRene H MedemaRoderick L BeijersbergenRene BernardsRodrigo Leite de OliveiraInducing 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.https://doi.org/10.1371/journal.pone.0273182 |
| spellingShingle | Ziva Pogacar Jackie L Johnson Lenno Krenning Giulia De Conti Fleur Jochems Cor Lieftink Arno Velds Leyma Wardak Kelvin Groot Arnout Schepers Liqin Wang Ji-Ying Song Marieke van de Ven Olaf van Tellingen Rene H Medema Roderick L Beijersbergen Rene Bernards Rodrigo Leite de Oliveira Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity. PLoS ONE |
| title | Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity. |
| title_full | Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity. |
| title_fullStr | Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity. |
| title_full_unstemmed | Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity. |
| title_short | Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity. |
| title_sort | indisulam synergizes with palbociclib to induce senescence through inhibition of cdk2 kinase activity |
| url | https://doi.org/10.1371/journal.pone.0273182 |
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