Pharmacological Targeting of P300/CBP Reveals EWS::FLI1-mediated Senescence Evasion in Ewing Sarcoma

Overview

Journal Mol Cancer

Publisher Biomed Central

Specialties Molecular Biology
Oncology

Date 2024 Oct 4

PMID 39367409

Authors

Erdong Wei

Ana Mitanoska

Quinn OBrien

Kendall Porter

MacKenzie Molina

Haseeb Ahsan

Usuk Jung

Lauren Mills

Michael Kyba

Darko Bosnakovski

Affiliations

Soon will be listed here.

Abstract

Ewing sarcoma (ES) poses a significant therapeutic challenge due to the difficulty in targeting its main oncodriver, EWS::FLI1. We show that pharmacological targeting of the EWS::FLI1 transcriptional complex via inhibition of P300/CBP drives a global transcriptional outcome similar to direct knockdown of EWS::FLI1, and furthermore yields prognostic risk factors for ES patient outcome. We find that EWS::FLI1 upregulates LMNB1 via repetitive GGAA motif recognition and acetylation codes in ES cells and EWS::FLI1-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.

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