1. Pharmacological targeting of P300/CBP reveals EWS::FLI1-mediated senescence evasion in Ewing sarcoma.
- Author
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Wei E, Mitanoska A, O'Brien Q, Porter K, Molina M, Ahsan H, Jung U, Mills L, Kyba M, and Bosnakovski D
- Subjects
- Humans, Cell Line, Tumor, Gene Expression Regulation, Neoplastic drug effects, Signal Transduction drug effects, Mesenchymal Stem Cells metabolism, Mesenchymal Stem Cells drug effects, E1A-Associated p300 Protein, Sarcoma, Ewing metabolism, Sarcoma, Ewing pathology, Sarcoma, Ewing drug therapy, Sarcoma, Ewing genetics, Proto-Oncogene Protein c-fli-1 metabolism, Proto-Oncogene Protein c-fli-1 genetics, RNA-Binding Protein EWS genetics, RNA-Binding Protein EWS metabolism, Cellular Senescence drug effects, p300-CBP Transcription Factors metabolism, p300-CBP Transcription Factors antagonists & inhibitors, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion metabolism
- 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., (© 2024. The Author(s).)
- Published
- 2024
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