PF576 NONSENSE‐MEDIATED MRNA DECAY IS A THERAPEUTIC TARGET IN MULTIPLE MYELOMA
Notice bibliographique
Résumé
Background: Nonsense‐mediated mRNA decay (NMD) is a translation‐coupled cellular quality control system that degrades mRNAs containing premature termination codons (PTCs) and regulates the expression of 5–10% of normal mRNAs. NMD prevents translation of misfolded proteins, thereby halting the potential activation of the unfolded protein response (UPR). Cancer cells display increased alternative splicing events and splicing factors are frequently mutated in cancer. This suggests that NMD, and its link with ER‐stress, might be therapeutically targetable in cancer. This notion was investigated, based on preliminary data showing that CC‐115, a known inhibitor of mTOR kinase (TORK) and DNA‐PK, also inhibits a key player in NMD activation. Aims: To explore the application of CC‐115 as a specific inhibitor of NMD in cancer. Methods: A comparative screen in 141 cancer cell lines was performed with CC‐115 versus specific inhibitors of TORK and DNA‐PK, using inhibition of proliferation (Cell‐Titer Glow) and cell death (apoptosis) as read‐out. Additional targets of CC‐115 were determined by ActivX KiNativ analysis, and confirmed by knockdown and additional kinase inhibitors. Dependence of CC‐115 sensitivity on specific genes was determined by CRISPR/Cas9 technology in various multiple myeloma (MM) cell lines. RNA sequencing was used for identification of potential targets in 3 sensitive and 3 resistant cell lines and confirmed by qPCR. Activity in vivo was tested in xenograft tumors. Results: ActivX KiNativ analysis revealed NMD inhibition as an additional target of CC‐115. NMD inhibition with CC‐115 resulted in a decreased phosphorylation of UPF1 and a dose dependent increase of NMD sensitive transcripts. CC‐115 activated the PERK branch of the UPR, as evidenced by increased mRNA expression of ATF4 , ATF3 and CHOP, while HSPA5 and sXBP1 were not affected. Cell death analyses among various B cell lines showed that MM cell lines were in general highly sensitive to CC‐115. Activity of CC‐115 correlated strongly with cell death by the known ER‐stress inducer, thapsigargin. Cell death by CC‐115 occurred via the mitochondrial pathway of apoptosis, as it depended on caspase activity and the presence of Bax‐Bak. RNA sequencing indicated that CC‐115‐sensitive cell lines had a lower baseline expression of cytoskeleton and vesicle transport genes and a higher expression of genes involved in SMAD and BMP signaling. Gene set enrichment analysis revealed an overrepresentation of MYC downstream targets, oxidative phosphorylation and UPR genes in CC‐115 sensitive vs. resistant cell lines, and confirmed the inhibitory effects of CC‐115 on NMD. Lastly, antitumor effects of CC‐115 were superior to specific TORK inhibition in xenograft mice, without general toxicity. Summary/Conclusion: Hematologic tumors with high protein production are highly sensitive to CC‐115, a clinically exploitable inhibitor of NMD. This might be particularly interesting in hematologic malignancies such as multiple myeloma, that depend on NMD to avoid excessive protein stress.
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| 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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 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 tête enseignante, 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 ».