Abstract 2468: Combined targeting of the EWS/ETS transcriptional program by BET bromodomain and PI3K pathway inhibition blocks tumorigenicity and increases apoptosis in Ewing sarcoma
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Title:
Abstract 2468: Combined targeting of the EWS/ETS transcriptional program by BET bromodomain and PI3K pathway inhibition blocks tumorigenicity and increases apoptosis in Ewing sarcoma
Description:
<jats:title>Abstract</jats:title>
<jats:p>Ewing sarcomas (ES) are highly malignant bone or soft tissue tumors. Genetically, ES are defined by balanced chromosomal EWS/ETS translocations that give rise to chimeric proteins (EWS-ETS), which generate an oncogenic transcriptional program associated with altered epigenetic marks throughout the genome.</jats:p>
<jats:p>By use of an inhibitor (JQ1) blocking BET bromodomain binding proteins (BRDs) we strikingly observed a strong down-regulation of the predominant EWS-ETS protein EWS-FLI1 in a dose dependent manner. This was further enhanced by co-treatment with an inhibitor (BEZ235) of the PI3K pathway. Microarray analysis revealed JQ1 treatment to block a typical ES associated expression program. The effect on this expression program was mimicked by RNA interference of BRD3 or BRD4 expression but not by BRD2 blockade, indicating that the EWS-FLI1 mediated expression profile is at least in part mediated via such epigenetic readers.</jats:p>
<jats:p>JQ1 treatment not only suppressed an ES specific expression profile but also blocked contact dependent and independent proliferation of different ES lines. But subsequent analysis of proliferation after transient knockdown of either BRD3 or BRD4 did not recapitulate inhibition of proliferation as observed after JQ1 treatment, indicating the necessary simultaneous blockade of both proteins. However, inhibition of proliferation after JQ1 treatment was due to a partial G1 arrest and S phase elongation of the cell cycle. In addition, induction of apoptosis as demonstrated by PARP1-, CASP7-cleavage and increased CASP3 activity significantly contributed to the reduction of the proliferative ability of ES lines. Single or combination treatment with the PI3K/mTOR inhibitor BEZ235 increased apoptosis of ES cell lines although single treatment with BEZ235 was less effective than JQ1 application. Consequently, tumor development was dose dependently suppressed with increased formation of apoptotic bodies in a xeno-transplant model in immune deficient mice, overall indicating that ES may be susceptible to treatment with epigenetic inhibitors blocking BET bromodomain activity and the associated pathognomonic EWS-ETS transcriptional program.</jats:p>
<jats:p>Citation Format: Tim Hensel, Chiara Giorgi, Fiona Becker-Dettling, Julia Calzada-Wack, Frauke Neff, Thorsten Buch, Oxana Schmidt, Beat W. Schäfer, Stefan Burdach, Günther HS Richter. Combined targeting of the EWS/ETS transcriptional program by BET bromodomain and PI3K pathway inhibition blocks tumorigenicity and increases apoptosis in Ewing sarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2468.</jats:p>