Pharmacological targeting of P300/CBP reveals EWS::FLI1-mediated senescence evasion in Ewing sarcoma.

ABSTRACT

Ewing sarcoma (ES) poses a significant therapeutic challenge due to the difficulty in targeting its main oncodriver, EWSFLI1. We show that pharmacological targeting of the EWSFLI1 transcriptional complex via inhibition of P300/CBP drives a global transcriptional outcome similar to direct knockdown of EWSFLI1, and furthermore yields prognostic risk factors for ES patient outcome. We find that EWSFLI1 upregulates LMNB1 via repetitive GGAA motif recognition and acetylation codes in ES cells and EWSFLI1-permissive mesenchymal stem cells, which when reversed by P300 inhibition leads to senescence of ES cells. P300-inhibited senescent ES cells can then be eliminated by senolytics targeting the PI3K signaling pathway. The vulnerability of ES cells to this combination therapy suggests an appealing synergistic strategy for future therapeutic exploration.