Braegelmann, Johannes, Dammert, Marcel A., Dietlein, Felix, Heuckmann, Johannes M., Choidas, Axel, Boehm, Stefanie, Richters, Andre, Basu, Debjit, Tischler, Verena ORCID: 0000-0002-6673-8329, Lorenz, Carina, Habenberger, Peter, Fang, Zhizhou, Ortiz-Cuaran, Sandra, Leenders, Frauke, Eickhoff, Jan, Koch, Uwe, Getlik, Matthaeus, Termathe, Martin ORCID: 0000-0002-5618-4633, Sallouh, Muhammad, Greff, Zoltan, Varga, Zoltan, Balke-Want, Hyatt, French, Christopher A., Peifer, Martin ORCID: 0000-0002-5243-5503, Reinhardt, H. Christian, Orfi, Laszlo ORCID: 0000-0001-6149-2385, Keri, Gyorgy, Ansen, Sascha, Heukamp, Lukas C., Buettner, Reinhard, Rauh, Daniel, Klebl, Bert M., Thomas, Roman K. and Sos, Martin L. (2017). Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline Carcinoma. Cell Reports, 20 (12). S. 2833 - 2846. CAMBRIDGE: CELL PRESS. ISSN 2211-1247

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Braegelmann, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dammert, Marcel A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dietlein, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heuckmann, Johannes M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Choidas, AxelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boehm, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richters, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Basu, DebjitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tischler, VerenaUNSPECIFIEDorcid.org/0000-0002-6673-8329UNSPECIFIED
Lorenz, CarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Habenberger, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fang, ZhizhouUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ortiz-Cuaran, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leenders, FraukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eickhoff, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koch, UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Getlik, MatthaeusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Termathe, MartinUNSPECIFIEDorcid.org/0000-0002-5618-4633UNSPECIFIED
Sallouh, MuhammadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Greff, ZoltanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Varga, ZoltanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Balke-Want, HyattUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
French, Christopher A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, MartinUNSPECIFIEDorcid.org/0000-0002-5243-5503UNSPECIFIED
Reinhardt, H. ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Orfi, LaszloUNSPECIFIEDorcid.org/0000-0001-6149-2385UNSPECIFIED
Keri, GyorgyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ansen, SaschaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heukamp, Lukas C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rauh, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klebl, Bert M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sos, Martin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-217577
DOI: 10.1016/j.celrep.2017.08.082
Journal or Publication Title: Cell Reports
Volume: 20
Number: 12
Page Range: S. 2833 - 2846
Date: 2017
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 2211-1247
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
RNA-POLYMERASE-II; 1ST-LINE TREATMENT; P-TEFB; TRANSCRIPTION; BRAF; MYC; DIFFERENTIATION; CHEMOTHERAPY; SPECIFICITY; LANDSCAPEMultiple languages
Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/21757

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