Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline Carcinoma

Publication date: 19 September 2017
Source:Cell Reports, Volume 20, Issue 12
Author(s): 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
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.

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Teaser

By screening 1,505 compounds against 78 cancer cell lines, Brägelmann et al. identify a specific sensitivity of BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells to CDK9 inhibition. CDK9 inhibition affects transcriptional elongation, de-regulates MYC signaling, and induces apoptosis by suppressing anti-apoptotic MCL1. CDK9 may thus be a promising target in NMC.


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