Bibliographic Details
| Title: |
Pharmacological targeting of P300/CBP reveals EWS::FLI1-mediated senescence evasion in Ewing sarcoma |
| Authors: |
Erdong Wei, Ana Mitanoska, Quinn O’Brien, Kendall Porter, MacKenzie Molina, Haseeb Ahsan, Usuk Jung, Lauren Mills, Michael Kyba, Darko Bosnakovski |
| Source: |
Molecular Cancer, Vol 23, Iss 1, Pp 1-22 (2024) |
| Publisher Information: |
BMC, 2024. |
| Publication Year: |
2024 |
| Collection: |
LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
| Subject Terms: |
Ewing sarcoma, EWS::FLI1, Lamin B1, P300/CBP, Senescence, Senolytics, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282 |
| More Details: |
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. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
1476-4598 |
| Relation: |
https://doaj.org/toc/1476-4598 |
| DOI: |
10.1186/s12943-024-02115-7 |
| Access URL: |
https://doaj.org/article/3923b7e698e143889b1d963ad608e92e |
| Accession Number: |
edsdoj.3923b7e698e143889b1d963ad608e92e |
| Database: |
Directory of Open Access Journals |
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