Combined inhibition of epigenetic readers and transcription initiation targets the EWS-ETS transcriptional program in Ewing sarcoma

  • Background: Previously, we used inhibitors blocking BET bromodomain binding proteins (BRDs) in Ewing sarcoma (EwS) and observed that long term treatment resulted in the development of resistance. Here, we analyze the possible interaction of BRD4 with cyclin-dependent kinase (CDK) 9. Methods: Co-immunoprecipitation experiments (CoIP) to characterize BRD4 interaction and functional consequences of inhibiting transcriptional elongation were assessed using drugs targeting of BRD4 or CDK9, either alone or in combination. Results: CoIP revealed an interaction of BRD4 with EWS-FLI1 and CDK9 in EwS. Treatment of EwS cells with CDKI-73, a specific CDK9 inhibitor (CDK9i), induced a rapid downregulation of EWS-FLI1 expression and block of contact-dependent growth. CDKI-73 induced apoptosis in EwS, as depicted by cleavage of Caspase 7 (CASP7), PARP and increased CASP3 activity, similar to JQ1. Microarray analysis following CDKI-73 treatment uncovered a transcriptional program that was only partially comparable to BRD inhibition. Strikingly, combined treatment of EwS with BRD- and CDK9-inhibitors re-sensitized cells, and was overall more effective than individual drugs not only in vitro but also in a preclinical mouse model in vivo. Conclusion: Treatment with BRD inhibitors in combination with CDK9i offers a new treatment option that significantly blocks the pathognomonic EWS-ETS transcriptional program and malignant phenotype of EwS.

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Author:Günther H. S. Richter, Tim Hensel, Oxana Schmidt, Vadim Saratov, Kristina von Heyking, Fiona Becker-Dettling, Carolin Prexler, Hsi-Yu Yen, Katja Steiger, Simone FuldaORCiDGND, Uta DirksenORCiDGND, Wilko WeichertGND, Shudong Wang, Stefan Burdach, Beat W. Schäfer
URN:urn:nbn:de:hebis:30:3-544364
DOI:https://doi.org/10.3390/cancers12020304
ISSN:2072-6694
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/32012890
Parent Title (English):Cancers
Publisher:MDPI
Place of publication:Basel
Document Type:Article
Language:English
Date of Publication (online):2020/01/28
Date of first Publication:2020/01/28
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/04/09
Tag:BRD4; CDK9; Ewing sarcoma; combination therapy; tumor growth
Volume:12
Issue:304
Page Number:17
Note:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
HeBIS-PPN:463771672
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0