Cell Reports (Sep 2017)
Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline Carcinoma
- 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
Affiliations
- Johannes Brägelmann
- Molecular Pathology, Institute of Pathology, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
- Marcel A. Dammert
- Molecular Pathology, Institute of Pathology, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
- Felix Dietlein
- Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
- Johannes M. Heuckmann
- NEO New Oncology GmbH, Gottfried-Hagen-Str. 20, 51105 Cologne, Germany
- Axel Choidas
- Lead Discovery Center (LDC) GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany
- Stefanie Böhm
- Molecular Pathology, Institute of Pathology, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
- André Richters
- Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44221 Dortmund, Germany
- Debjit Basu
- Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44221 Dortmund, Germany
- Verena Tischler
- Department of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany
- Carina Lorenz
- Molecular Pathology, Institute of Pathology, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
- Peter Habenberger
- Lead Discovery Center (LDC) GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany
- Zhizhou Fang
- Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44221 Dortmund, Germany
- Sandra Ortiz-Cuaran
- Department of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany
- Frauke Leenders
- Department of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany
- Jan Eickhoff
- Lead Discovery Center (LDC) GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany
- Uwe Koch
- Lead Discovery Center (LDC) GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany
- Matthäus Getlik
- Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44221 Dortmund, Germany
- Martin Termathe
- Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44221 Dortmund, Germany
- Muhammad Sallouh
- Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44221 Dortmund, Germany
- Zoltán Greff
- Vichem Chemie Research Ltd., Herman Ottó u. 15, Budapest, Hungary
- Zoltán Varga
- Vichem Chemie Research Ltd., Herman Ottó u. 15, Budapest, Hungary
- Hyatt Balke-Want
- Department of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany
- Christopher A. French
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Martin Peifer
- Department of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany
- H. Christian Reinhardt
- Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
- László Örfi
- Vichem Chemie Research Ltd., Herman Ottó u. 15, Budapest, Hungary
- György Kéri
- Vichem Chemie Research Ltd., Herman Ottó u. 15, Budapest, Hungary
- Sascha Ansén
- Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
- Lukas C. Heukamp
- Department of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany
- Reinhard Büttner
- Institute of Pathology, Medical Faculty, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
- Daniel Rauh
- Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, 44221 Dortmund, Germany
- Bert M. Klebl
- Lead Discovery Center (LDC) GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany
- Roman K. Thomas
- Department of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany
- Martin L. Sos
- Molecular Pathology, Institute of Pathology, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
- DOI
- https://doi.org/10.1016/j.celrep.2017.08.082
- Journal volume & issue
-
Vol. 20,
no. 12
pp. 2833 – 2845
Abstract
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.
Keywords
