Abstract 1844: Anti-tumor activity of a dual BET/CBP/EP300 inhibitor, NEO2734, in undifferentiated pleomorphic sarcomas and identification of genes involved in resistance
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".