TY  - JOUR
A1  - Richter, Günther H. S.
A1  - Hensel, Tim
A1  - Schmidt, Oxana
A1  - Saratov, Vadim
A1  - Heyking, Kristina von
A1  - Becker-Dettling, Fiona
A1  - Prexler, Carolin
A1  - Yen, Hsi-Yu
A1  - Steiger, Katja
A1  - Fulda, Simone
A1  - Dirksen, Uta
A1  - Weichert, Wilko
A1  - Wang, Shudong
A1  - Burdach, Stefan
A1  - Schäfer, Beat W.
T1  - Combined inhibition of epigenetic readers and transcription initiation targets the EWS-ETS transcriptional program in Ewing sarcoma
T2  - Cancers
N2  - 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.
KW  - Ewing sarcoma
KW  - tumor growth
KW  - CDK9
KW  - BRD4
KW  - combination therapy
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/54436
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-544364
SN  - 2072-6694
N1  - 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.
VL  - 12
IS  - 304
PB  - MDPI
CY  - Basel
ER  -