Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline Carcinoma
Kinase inhibitors represent the backbone of targeted cancer therapy, yet only a limited number of oncogenic drivers are directly druggable. By interrogating the activity of 1,505 kinase inhibitors, we found that BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells are specifically killed by CDK9 in...
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| Format: | Article |
| Language: | English |
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Elsevier
2017-09-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112471731224X |
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| author | Johannes Brägelmann Marcel A. Dammert Felix Dietlein Johannes M. Heuckmann Axel Choidas Stefanie Böhm André Richters Debjit Basu Verena Tischler Carina Lorenz Peter Habenberger Zhizhou Fang Sandra Ortiz-Cuaran Frauke Leenders Jan Eickhoff Uwe Koch Matthäus Getlik Martin Termathe Muhammad Sallouh Zoltán Greff Zoltán Varga Hyatt Balke-Want Christopher A. French Martin Peifer H. Christian Reinhardt László Örfi György Kéri Sascha Ansén Lukas C. Heukamp Reinhard Büttner Daniel Rauh Bert M. Klebl Roman K. Thomas Martin L. Sos |
| author_facet | Johannes Brägelmann Marcel A. Dammert Felix Dietlein Johannes M. Heuckmann Axel Choidas Stefanie Böhm André Richters Debjit Basu Verena Tischler Carina Lorenz Peter Habenberger Zhizhou Fang Sandra Ortiz-Cuaran Frauke Leenders Jan Eickhoff Uwe Koch Matthäus Getlik Martin Termathe Muhammad Sallouh Zoltán Greff Zoltán Varga Hyatt Balke-Want Christopher A. French Martin Peifer H. Christian Reinhardt László Örfi György Kéri Sascha Ansén Lukas C. Heukamp Reinhard Büttner Daniel Rauh Bert M. Klebl Roman K. Thomas Martin L. Sos |
| author_sort | Johannes Brägelmann |
| collection | DOAJ |
| description | Kinase inhibitors represent the backbone of targeted cancer therapy, yet only a limited number of oncogenic drivers are directly druggable. By interrogating the activity of 1,505 kinase inhibitors, we found that BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells are specifically killed by CDK9 inhibition (CDK9i) and depend on CDK9 and Cyclin-T1 expression. We show that CDK9i leads to robust induction of apoptosis and of markers of DNA damage response in NMC cells. While both CDK9i and bromodomain inhibition over time result in reduced Myc protein expression, only bromodomain inhibition induces cell differentiation and a p21-induced cell-cycle arrest in these cells. Finally, RNA-seq and ChIP-based analyses reveal a BRD4-NUT-specific CDK9i-induced perturbation of transcriptional elongation. Thus, our data provide a mechanistic basis for the genotype-dependent vulnerability of NMC cells to CDK9i that may be of relevance for the development of targeted therapies for NMC patients. |
| first_indexed | 2024-12-20T19:45:52Z |
| format | Article |
| id | doaj.art-65260813004b4d5e8d198b9f59d2baa6 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-20T19:45:52Z |
| publishDate | 2017-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-65260813004b4d5e8d198b9f59d2baa62022-12-21T19:28:25ZengElsevierCell Reports2211-12472017-09-0120122833284510.1016/j.celrep.2017.08.082Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline CarcinomaJohannes Brägelmann0Marcel A. Dammert1Felix Dietlein2Johannes M. Heuckmann3Axel Choidas4Stefanie Böhm5André Richters6Debjit Basu7Verena Tischler8Carina Lorenz9Peter Habenberger10Zhizhou Fang11Sandra Ortiz-Cuaran12Frauke Leenders13Jan Eickhoff14Uwe Koch15Matthäus Getlik16Martin Termathe17Muhammad Sallouh18Zoltán Greff19Zoltán Varga20Hyatt Balke-Want21Christopher A. French22Martin Peifer23H. Christian Reinhardt24László Örfi25György Kéri26Sascha Ansén27Lukas C. Heukamp28Reinhard Büttner29Daniel Rauh30Bert M. Klebl31Roman K. Thomas32Martin L. Sos33Molecular Pathology, Institute of Pathology, University of Cologne, Kerpener Str. 62, 50937 Cologne, GermanyMolecular Pathology, Institute of Pathology, University of Cologne, Kerpener Str. 62, 50937 Cologne, GermanyDepartment I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, GermanyNEO New Oncology GmbH, Gottfried-Hagen-Str. 20, 51105 Cologne, GermanyLead Discovery Center (LDC) GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, GermanyMolecular Pathology, Institute of Pathology, University of Cologne, Kerpener Str. 62, 50937 Cologne, GermanyFaculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44221 Dortmund, GermanyFaculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44221 Dortmund, GermanyDepartment of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, GermanyMolecular Pathology, Institute of Pathology, University of Cologne, Kerpener Str. 62, 50937 Cologne, GermanyLead Discovery Center (LDC) GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, GermanyFaculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44221 Dortmund, GermanyDepartment of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, GermanyDepartment of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, GermanyLead Discovery Center (LDC) GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, GermanyLead Discovery Center (LDC) GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, GermanyFaculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44221 Dortmund, GermanyFaculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44221 Dortmund, GermanyFaculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44221 Dortmund, GermanyVichem Chemie Research Ltd., Herman Ottó u. 15, Budapest, HungaryVichem Chemie Research Ltd., Herman Ottó u. 15, Budapest, HungaryDepartment of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, GermanyDepartment of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USADepartment of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, GermanyDepartment I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, GermanyVichem Chemie Research Ltd., Herman Ottó u. 15, Budapest, HungaryVichem Chemie Research Ltd., Herman Ottó u. 15, Budapest, HungaryDepartment I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, GermanyDepartment of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, GermanyInstitute of Pathology, Medical Faculty, University of Cologne, Kerpener Str. 62, 50937 Cologne, GermanyFaculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44221 Dortmund, GermanyLead Discovery Center (LDC) GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, GermanyDepartment of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, GermanyMolecular Pathology, Institute of Pathology, University of Cologne, Kerpener Str. 62, 50937 Cologne, GermanyKinase inhibitors represent the backbone of targeted cancer therapy, yet only a limited number of oncogenic drivers are directly druggable. By interrogating the activity of 1,505 kinase inhibitors, we found that BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells are specifically killed by CDK9 inhibition (CDK9i) and depend on CDK9 and Cyclin-T1 expression. We show that CDK9i leads to robust induction of apoptosis and of markers of DNA damage response in NMC cells. While both CDK9i and bromodomain inhibition over time result in reduced Myc protein expression, only bromodomain inhibition induces cell differentiation and a p21-induced cell-cycle arrest in these cells. Finally, RNA-seq and ChIP-based analyses reveal a BRD4-NUT-specific CDK9i-induced perturbation of transcriptional elongation. Thus, our data provide a mechanistic basis for the genotype-dependent vulnerability of NMC cells to CDK9i that may be of relevance for the development of targeted therapies for NMC patients.http://www.sciencedirect.com/science/article/pii/S221112471731224Xhigh-throughput screenNUT midline carcinomaCDK9 inhibitortranscriptional elongation |
| spellingShingle | Johannes Brägelmann Marcel A. Dammert Felix Dietlein Johannes M. Heuckmann Axel Choidas Stefanie Böhm André Richters Debjit Basu Verena Tischler Carina Lorenz Peter Habenberger Zhizhou Fang Sandra Ortiz-Cuaran Frauke Leenders Jan Eickhoff Uwe Koch Matthäus Getlik Martin Termathe Muhammad Sallouh Zoltán Greff Zoltán Varga Hyatt Balke-Want Christopher A. French Martin Peifer H. Christian Reinhardt László Örfi György Kéri Sascha Ansén Lukas C. Heukamp Reinhard Büttner Daniel Rauh Bert M. Klebl Roman K. Thomas Martin L. Sos Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline Carcinoma Cell Reports high-throughput screen NUT midline carcinoma CDK9 inhibitor transcriptional elongation |
| title | Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline Carcinoma |
| title_full | Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline Carcinoma |
| title_fullStr | Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline Carcinoma |
| title_full_unstemmed | Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline Carcinoma |
| title_short | Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline Carcinoma |
| title_sort | systematic kinase inhibitor profiling identifies cdk9 as a synthetic lethal target in nut midline carcinoma |
| topic | high-throughput screen NUT midline carcinoma CDK9 inhibitor transcriptional elongation |
| url | http://www.sciencedirect.com/science/article/pii/S221112471731224X |
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