Abstract 3265: PI3Kδ inhibitor, GS-1101, impacts transcription and translation in mantle cell lymphoma.
Notice bibliographique
Résumé
Abstract PI3Kα, β, γ and δ are the most ubiquitous and important PI3K family class I member isoforms that contribute to cell growth and survival processes in cancer. Among these isoforms, PI3Kα and β are broadly expressed, where PI3Kγ and δ are uniquely expressed in T- and B-cells, respectively, making them ideal candidates for targeted therapies in hematological malignancies. GS-1101, also known as CAL-101, is a potent and selective PI3Kδ inhibitor (IC50=2.5 nM) that is currently in Phase II/III clinical trials in B-cell diseases. Previous studies have elucidated disruption of survival factors and cytokine signaling mediated by PI3K/Akt pathways as major mechanism of activity in B-cell malignancies. It has been established that oncoprotein PI3Kα isoform deregulates transcription and translation processes in solid tumors, and based on the knowledge of PI3Kδ and GS-1101, we hypothesized that 1) GS-1101 treatment will inhibit gene transcription and protein translation, 2) will impact transcription and translation regulators that are downstream of PI3K/Akt pathways and 3) will reduce short-lived mRNA and proteins such as Mcl-1, c-Myc and cyclin D1, which are important in mantle cell lymphoma (MCL), a B-cell lymphoma. In JeKo-1 and Mino MCL cell lines, PI3Kδ is the most prominent isoform. In these cell lines and in primary MCL cells, the level of apoptosis was modest (less than 15%) when cells were treated with 5 μM GS-1101 for 24 hr. Consistent with Annexin/PI data, slight levels of PARP cleavage was detected. Of the two Akt phosphorylation sites, Thr308 and Ser473, phosphorylation of Akt (Thr308) showed dose-dependent decrease in both cell lines when treated by GS-1101 for 1 hr following serum starvation; however, there was no change in Akt (Ser347) levels following 24 hr of GS-1101 treatment in full serum conditions. Global RNA synthesis was substantially reduced in MCL primary samples, reaching 80% of control at 1 μM and 50% or less at 5 μM for 24 hr treatment, while only minor changes (80-90% of control) were observed in JeKo-1 and Mino. Global translation inhibition measured by leucine incorporation was observed in JeKo-1, Mino and primary MCL cells. Phosphorylation levels of translation regulators p70S6K (Ser9) and S6 (Ser235/236) showed dose-dependent decrease when treated with GS-1101 for 24 hr in JeKo-1. Meanwhile, minor decrease of 4E-BP1 (Ser65) phosphorylation level was observed in JeKo-1 under the same conditions. In Jeko-1 cells, early response genes such as short-lived MCL1 mRNA level was reduced following 24 hr of GS-1101 treatment, however, other (PIM2, MYC, CCND1) mRNA levels decreased to a lesser extent. At the protein level, both Mcl-1 and cyclin D1 expression decreased in JeKo-1 cells. In conclusion, similar to inhibition of other PI3K isoforms, PI3Kδ inhibition impacted transcription and translation, and reduced cyclin D1 and Mcl-1 levels which are important for MCL cell survival and proliferation. Citation Format: Qingshan Yang, Lisa S. Chen, Sattva S. Neelapu, Brian J. Lanutti, Varsha Gandhi. PI3Kδ inhibitor, GS-1101, impacts transcription and translation in mantle cell lymphoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3265. doi:10.1158/1538-7445.AM2013-3265
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) | 0,002 | 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 ».