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 GreffZoltán 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

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2833-2845
Number of pages13
JournalCell reports
Volume20
Issue number12
DOIs
StatePublished - Sep 19 2017

Bibliographical note

Funding Information:
We thank Prof. Oliver Gautschi (Cantonal Hospital Lucerne, Switzerland) for insightful discussions, Dr. Graziella Bosco (University of Cologne, Germany) for help with RNA-seq data processing, and Prof. Nicolaus Friedrich (University of Cologne, Germany) for immunohistological staining. We thank Prof. Qiang Zhou (University of California, Berkeley, USA) for providing FLAG-CDK9 constructs. B.M.K. dedicates this work to the memory of Dr. György Keri, CEO of Vichem and professor at the Semmelweis University, Budapest, Hungary. György recently lost his fight against cancer. He was a great scientist and a wonderful friend. We are also sad to announce that Z.G. passed away during the course of this project. With him we lost a productive researcher and much-valued colleague. This work was supported by the German federal state North Rhine Westphalia (NRW) as part of the FIT program (grant 314-4000-1209 to B.M.K. and LDC), by the European Union ( European Regional Development Fund: Investing In Your Future ) as part of the PerMed.NRW initiative (grant 005-1111-0025 to R.K.T., D.R., R.B., and LDC) and the EFRE initiative (grant EFFRE-0800397 to B.M.K., H.C.R., D.R., R.B., R.K.T., M.L.S., and LDC), by the German Ministry of Science and Education (BMBF) as part of the e:Med program (grants 01ZX1303 and 01ZX1603 to R.K.T., H.C.R., R.B., M.P., and D.R. and grant 01ZX1406 to M.L.S. and M.P.), by the German Consortium for Translational Cancer Research (DKTK) Joint Funding program (to R.K.T.), and by the BMBF as part of the NGFNplus program (grant 01GS08100 to R.K.T.). F.D. was supported by the Mildred-Scheel-Doktorandenprogramm of the Max-Planck Society (grant 110770 to F.D. and R.K.T.). V.T. is the recipient of a joint ERS/EMBO Long-Term Research Fellowship ( LTRF 2014-2951 ) and a Swiss Cancer League postdoctoral research fellowship ( BIL KFS-3402-02-2014 ). R.K.T. is a consultant of NEO New Oncology GmbH and received honoraria from AstraZeneca, Bayer, NEO New Oncology GmbH, Boehringer Ingelheim, Clovis Oncology, Daiichi-Sankyo, Eli Lilly, Johnson & Johnson (J&J), Merck KGaA, MSD, Puma, Roche, and Sanofi. J.M.H. is a full-time employee and co-founder of NEO New Oncology GmbH. M.L.S. received a commercial research grant from Novartis. A.C., R.K.T., P.H., B.M.K., J.E., and J.M.H. hold the patent “CDK9 inhibitors in the treatment of midline carcinoma.” R.B. has received honoraria for invited lectures and participation in SABs from Roche, Pfizer, Novartis, Boehringer-Ingelheim, Eli Lilly, Merck-Serono, and Qiagen. R.B. is a co-founder and serves as the chief scientific advisor of Targos Molecular Pathology Inc. (Kassel, Germany). D.R. reports consulting and lecture fees (Sanofi-Aventis, Astra-Zeneca, Novartis, Pfizer, Takeda, and Boehringer) and research support (MSD, Bayer Health Care, Merck-Serono, Bayer Crop Science, and J&J). H.C.R. received consulting and lecture fees (Merck, Celgene). A.C., P.H., J.E., U.K., and B.M.K. are employees of LDC, which has several commercial agreements in place with pharmaceutical companies.

Publisher Copyright:
© 2017 The Authors

Keywords

  • CDK9 inhibitor
  • NUT midline carcinoma
  • high-throughput screen
  • transcriptional elongation

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