Dual inhibition of BET and EP300 has antitumor activity in undifferentiated pleomorphic sarcomas and synergizes with ferroptosis induction
Undifferentiated pleomorphic sarcoma (UPS) is the most frequent and the most aggressive sarcoma subtype for which therapeutic options are limited. The identification of new therapeutic strategies is therefore an important medical need. Epigenetic modifiers has been extensively investigated in recent...
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Elsevier
2025-02-01
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| Series: | Translational Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523324003620 |
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| author | Stéphanie Verbeke Aurélien Bourdon Mathilde Lafon Vanessa Chaire Bertolo Frederic Amina Naït Eldjoudi Marie-Alix Derieppe Francis Giles Antoine Italiano |
| author_facet | Stéphanie Verbeke Aurélien Bourdon Mathilde Lafon Vanessa Chaire Bertolo Frederic Amina Naït Eldjoudi Marie-Alix Derieppe Francis Giles Antoine Italiano |
| author_sort | Stéphanie Verbeke |
| collection | DOAJ |
| description | Undifferentiated pleomorphic sarcoma (UPS) is the most frequent and the most aggressive sarcoma subtype for which therapeutic options are limited. The identification of new therapeutic strategies is therefore an important medical need. Epigenetic modifiers has been extensively investigated in recent years leading to the development of novel therapeutic agents. Dual BET/EP300 inhibitors have shown synergistic antitumor activity and have recently entered clinical development. To date, no data related to potential of BET/EP300 inhibition as a treatment in UPS have been reported. To investigate the therapeutic potential of BET/EP300 inhibition, we evaluated the antitumor activity of three compounds in vitro via MTT, apoptosis and cell cycle assays. The most potent inhibitor was evaluated in vivo in two animal models and the mechanisms of action were investigated by RNA sequencing, Western blotting and immunofluorescence staining. A CRISPR knockout screen was performed to identify resistance mechanisms. Among the three compounds tested, the dual inhibitor NEO2734 was the most potent, decreased the viability of UPS cells in vitro through a regulation of E2F targets and cell cycle and decreased the tumor growth in vivo. Moreover, we identified GPX4 as a gene involved in resistance and showed synergy between BET inhibition and ferroptosis induction.The present study demonstrated that dual BET/EP300 inhibitors have a relevant antitumor activity in a subgroup of UPS characterized by expression of MYC-targets pathway and identified a potent combination therapeutic strategy that deserves further investigation in the clinical setting. |
| format | Article |
| id | doaj-art-62d49593b9bd4936b2e9578a460027b6 |
| institution | Kabale University |
| issn | 1936-5233 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj-art-62d49593b9bd4936b2e9578a460027b62025-01-22T05:41:25ZengElsevierTranslational Oncology1936-52332025-02-0152102236Dual inhibition of BET and EP300 has antitumor activity in undifferentiated pleomorphic sarcomas and synergizes with ferroptosis inductionStéphanie Verbeke0Aurélien Bourdon1Mathilde Lafon2Vanessa Chaire3Bertolo Frederic4Amina Naït Eldjoudi5Marie-Alix Derieppe6Francis Giles7Antoine Italiano8Sarcoma Unit, Bergonié Institute 33000 Bordeaux, France; INSERM U1312 BRIC BoRdeaux Institute of onCology, University of Bordeaux 33000 Bordeaux, FranceSarcoma Unit, Bergonié Institute 33000 Bordeaux, France; INSERM U1312 BRIC BoRdeaux Institute of onCology, University of Bordeaux 33000 Bordeaux, FranceSarcoma Unit, Bergonié Institute 33000 Bordeaux, France; INSERM U1312 BRIC BoRdeaux Institute of onCology, University of Bordeaux 33000 Bordeaux, FranceSarcoma Unit, Bergonié Institute 33000 Bordeaux, France; INSERM U1312 BRIC BoRdeaux Institute of onCology, University of Bordeaux 33000 Bordeaux, FranceSarcoma Unit, Bergonié Institute 33000 Bordeaux, France; INSERM U1312 BRIC BoRdeaux Institute of onCology, University of Bordeaux 33000 Bordeaux, FranceSarcoma Unit, Bergonié Institute 33000 Bordeaux, France; INSERM U1312 BRIC BoRdeaux Institute of onCology, University of Bordeaux 33000 Bordeaux, FranceService Commun des Animaleries, University of Bordeaux 33000 Bordeaux, FranceEpigene Therapeutics, Saint Laurent QC, CanadaSarcoma Unit, Bergonié Institute 33000 Bordeaux, France; INSERM U1312 BRIC BoRdeaux Institute of onCology, University of Bordeaux 33000 Bordeaux, France; Faculty of Medicine, University of Bordeaux 33000 Bordeaux, France; Corresponding author: Institut Bergonié, 229 cours de l'Argonne 33000 Bordeaux, France.Undifferentiated pleomorphic sarcoma (UPS) is the most frequent and the most aggressive sarcoma subtype for which therapeutic options are limited. The identification of new therapeutic strategies is therefore an important medical need. Epigenetic modifiers has been extensively investigated in recent years leading to the development of novel therapeutic agents. Dual BET/EP300 inhibitors have shown synergistic antitumor activity and have recently entered clinical development. To date, no data related to potential of BET/EP300 inhibition as a treatment in UPS have been reported. To investigate the therapeutic potential of BET/EP300 inhibition, we evaluated the antitumor activity of three compounds in vitro via MTT, apoptosis and cell cycle assays. The most potent inhibitor was evaluated in vivo in two animal models and the mechanisms of action were investigated by RNA sequencing, Western blotting and immunofluorescence staining. A CRISPR knockout screen was performed to identify resistance mechanisms. Among the three compounds tested, the dual inhibitor NEO2734 was the most potent, decreased the viability of UPS cells in vitro through a regulation of E2F targets and cell cycle and decreased the tumor growth in vivo. Moreover, we identified GPX4 as a gene involved in resistance and showed synergy between BET inhibition and ferroptosis induction.The present study demonstrated that dual BET/EP300 inhibitors have a relevant antitumor activity in a subgroup of UPS characterized by expression of MYC-targets pathway and identified a potent combination therapeutic strategy that deserves further investigation in the clinical setting.http://www.sciencedirect.com/science/article/pii/S1936523324003620BETSarcomaFerroptosisCRISPR screen |
| spellingShingle | Stéphanie Verbeke Aurélien Bourdon Mathilde Lafon Vanessa Chaire Bertolo Frederic Amina Naït Eldjoudi Marie-Alix Derieppe Francis Giles Antoine Italiano Dual inhibition of BET and EP300 has antitumor activity in undifferentiated pleomorphic sarcomas and synergizes with ferroptosis induction Translational Oncology BET Sarcoma Ferroptosis CRISPR screen |
| title | Dual inhibition of BET and EP300 has antitumor activity in undifferentiated pleomorphic sarcomas and synergizes with ferroptosis induction |
| title_full | Dual inhibition of BET and EP300 has antitumor activity in undifferentiated pleomorphic sarcomas and synergizes with ferroptosis induction |
| title_fullStr | Dual inhibition of BET and EP300 has antitumor activity in undifferentiated pleomorphic sarcomas and synergizes with ferroptosis induction |
| title_full_unstemmed | Dual inhibition of BET and EP300 has antitumor activity in undifferentiated pleomorphic sarcomas and synergizes with ferroptosis induction |
| title_short | Dual inhibition of BET and EP300 has antitumor activity in undifferentiated pleomorphic sarcomas and synergizes with ferroptosis induction |
| title_sort | dual inhibition of bet and ep300 has antitumor activity in undifferentiated pleomorphic sarcomas and synergizes with ferroptosis induction |
| topic | BET Sarcoma Ferroptosis CRISPR screen |
| url | http://www.sciencedirect.com/science/article/pii/S1936523324003620 |
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