Abstract 1844: Anti-tumor activity of a dual BET/CBP/EP300 inhibitor, NEO2734, in undifferentiated pleomorphic sarcomas and identification of genes involved in resistance
Notice bibliographique
Résumé
Abstract Introduction: Undifferentiated pleomorphic sarcoma is the most frequent and the most aggressive sarcoma subtype. Despite adequate locoregional treatment, up to 40% will develop metastatic disease. Doxorubicin represents the standard 1st line of treatment for patient with advanced disease. However, its activity is limited with a response rate of only 10% and a progression-free survival of less than 6-months. Identification of new therapeutic strategies is therefore an important medical need. Bromodomain and extra-terminal domain (BET) proteins, cyclic adenosine monophosphate response element-binding protein (CBP), and the E1A-binding protein of p300 (EP300) are important players in histone acetylation. BET inhibitors have already shown pre-clinical activity in translocation-related sarcomas such as Ewing tumors. However, BET and dual BET/P300 inhibitors could have also relevant anti-tumor activity if MYC driven tumors. We previously found that at least a subgroup of UPS is characterized by a strong expression of MYC-targets pathway (Toulmonde et al, EBIOMEDICINE, 2020) Methods: The anti-tumor activity of three compounds which inhibits either CBP/P300 only (CPI-637) or dual inhibitors of both BET and CBP/P300 proteins (NEO1132 and NEO2437) was investigated in four UPS cell lines and two patient-derived xenografts (PDX) established at Institut Bergonié (Bordeaux, France). A CRISPR-KO screen was used to identify genes that mediate resistance to NEO2734. Results: We found that the 3 compounds act mainly by inhibiting the cell cycle with a concomitant reduction of MYC expression. NEO2734 was the most potent one with IC50 range between 0.2 to 1 µM in vitro and an antitumor activity in vivo in the two PDX models of UPS. To investigate the mechanism of action, we performed a transcriptomic analysis by RNA-sequencing. Gene set enrichment analysis revealed that NEO2734 induced a downregulation of G2M checkpoint and E2F targets hallmarks. We confirmed these results at the protein level showing a downregulation of several proteins involved in these pathways such as PLK1, AURKA or CCNB1. Interestingly, two of our four UPS cells lines were resistant to NEO2734 (IC50 27µM and 73µM). To elucidate the genetic factors involved in this resistance, we performed a CRISPR-KO screen. We identified more than 200 genes as potential candidates involved in drug resistance and decided to focus on hnRNPU which is an interactor of P300 and play a role in cell cycle regulation through the formation of the mitotic spindle with PLK1 and AURKA. Conclusion: Dual inhibition of BET and CBP/P300 proteins has promising antitumor activity in undifferentiated pleomorphic sarcoma. Suppressing hnRNPU may enhance the activity of dual BET and P300/CBP bromodomain inhibitor in sarcoma and other cancers. Citation Format: Stephanie Verbeke, Frederic Bertolo, Vanessa Chaire, Aurelien Bourdon, Amina Naït Eldjoudi, Marie-Alix Derieppe, Francis Giles, Antoine Italiano. Anti-tumor activity of a dual BET/CBP/EP300 inhibitor, NEO2734, in undifferentiated pleomorphic sarcomas and identification of genes involved in resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1844.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».