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

Ewing Sarcoma (ES) poses a significant therapeutic challenge due to the difficulty in targeting its mainoncodriver, EWS::FLI1. We show that pharmacological targeting of the EWS::FLI1 transcriptionalcomplex via inhibition of P300/CBP drives a global transcriptional outcome similar to direct knockdownof EWS::FLI1, and furthermore yields prognostic risk factors for ES patient outcome. We find thatEWS::FLI1 upregulates LMNB1 via repetitive GGAA motif recognition and acetylation codes in EScells and EWS::FLI1-permissive mesenchymal stem cells, which when reversed by P300 inhibitionleads to senescence of ES cells. P300-inhibited senescent ES cells can then be eliminated by senolyticstargeting the PI3K signaling pathway. The vulnerability of ES cells to this combination therapy suggestsan appealing synergistic strategy for future therapeutic exploration.