Abstract 3867: Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy to reactivate p53 in high-risk neuroblastoma
Notice bibliographique
Résumé
Abstract Neuroblastoma (NB) is considered a failure of sympathoadrenal differentiation. High-risk neuroblastoma (HR-NB) is an aggressive pediatric tumor accounting for 15% of all pediatric oncology deaths. Less than 50% of HR-NB patients have long-term survival, despite intense multimodality treatment. Given the paucity of druggable mutations and findings that epigenetic drivers contribute to NB tumorigenesis, we undertook a chromatin-focused siRNA screen to uncover epigenetic regulators critical for survival of high-risk NBs. Of the 400 genes analyzed, high-content Opera imaging identified 53 genes whose loss of expression led to significant decreases in NB cell number with 16 also inducing differentiation. A screen with 21 epigenetic compounds in 8 NB cell lines and 2 non-transformed cell lines prioritized those siRNA hits with active tool compounds in the drug development pipeline. This revealed UNC0379 (targets SETD8) inhibited NB cell growth and identified SETD8 as an important and druggable NB target. SETD8 is the H4K20me1 methyltransferase which regulates DNA replication, chromosome condensation and gene expression. Analysis of primary NB revealed that high expression of SETD8 is associated with poor prognosis in NB (R2 platform ex. Kocak; p=1.4e-07). Levels of SETD8 were not significantly different between Stage 4 MYCN-amp compared to MYCN-WT tumors but high SETD8 levels were only associated with poor prognosis in the Stage 4 MYCN-WT(p=0.03). To understand SETD8-mechanism of action, we performed RNA-seq transcriptome analyses after genetic or pharmacological inhibition of SETD8. Ingenuity Pathway Analysis revealed that SETD8 ablation rescued p53 pro-apoptotic and cell-cycle arrest functions by activating the canonical p53 pathway. Functional studies showed SETD8 methylates p53 (K382) leading to its inactivation. Levels of p53K382me1 are higher in MYCN-WT NB cell lines compared to those with MYCN-amp. Less than 2% of NB tumors have p53 mutations but multiple mechanisms have been identified in MYCN-amp NB that functionally inactivate p53. This study identified that SETD8 inactivates p53 in NB and may be an important mechanism to inactivate p53 in MYCN-WT HR-NB. This subgroup represents 60-70% of HR-NB tumors. SETD8 inhibition led to increases in caspase-dependent cell death only in p53-WT but not -mutant or -null NB cells. Genetic rescue experiments confirmed that SETD8-induced cell death is p53 dependent and p53K382 is important for this activity. Our in vivo xenograft NB models, showed that genetic or pharmacologic (UNC0379) inhibition of SETD8 confers a significant survival advantage. This work identifies that SETD8 is a novel therapeutic target and its inhibition may be especially relevant for the subset of high-risk NB tumors with wildtype MYCN. This is the first in vivo preclinical study showing that targeting SETD8 inhibits tumor growth. Citation Format: Veronica Veschi, Zhihui Liu, Ty C. Voss, Laurent Ozbun, Berkley Gryder, Chunhua Yan, Ying Hu, Anqi Ma, Jian Jin, Sharlyn J. Mazur, Norris Lam, Barbara K. Souza, Giuseppe Giannini, Gordon L. Hager, Cheryl H. Arrowsmith, Javed Khan, Ettore Appella, Carol Thiele. Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy to reactivate p53 in high-risk neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3867. doi:10.1158/1538-7445.AM2017-3867
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) | 0,005 | 0,001 |
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 ».