Abstract 151: Inhibition of AKT-1 for the treatment of human non-small cell lung cancer (NSCLC) in-vitro
Notice bibliographique
Résumé
Abstract AKT is a serine-threonine kinase implicated in tumorigenesis as a central regulator of cellular growth, proliferation, survival, metabolism, and migration. Activated AKT is overexpressed in 50-70% of NSCLC tumors and has exhibited an association with poor prognosis as well as chemotherapeutic resistance to platinum-based therapy. Accordingly, AKT inhibitors such as MK-2206 are currently undergoing clinical investigation for the treatment of human NSCLC however, these agents broadly target all three (1-3) AKT isoforms. Recent evidence suggests opposing roles of the AKT isoforms in tumorigenesis where loss of AKT-1 inhibits while the loss of AKT-2 enhances lung tumor development in transgenic mouse models. Based on these findings, we hypothesized that preferential inhibition of AKT-1 would warrant a more effective therapeutic strategy for NSCLC compared to the current clinical approach of broad AKT inhibition. WST-1 cell viability assays have revealed that a selective AKT-1 inhibitor A-674563 is a more potent regulator of survival in 6 NSCLC cell lines compared to a pan-AKT inhibitor MK-2206. Furthermore, off-target CDK2 inhibition likely contributes to the observed benefits of the AKT-1 inhibitor as the reduction in cell viability largely parallels the effects of a CDK2 inhibitor PHA-848125. In addition, the cell lines with higher endogenous CDK2 and p-CDK2 expression are more sensitive to the AKT-1 inhibitor relative to the pan-AKT inhibitor MK-2206. Basal protein and RNA levels in each of the cell lines have also shown that high AKT-3 expression may confer resistance to the pan-AKT inhibitor MK-2206. Thus, AKT-3 expression has the potential to serve as a predictive marker for patient response to AKT-1 versus broad AKT-inhibition. Cell cycle analysis demonstrated that the AKT-1 inhibitor decreases the proportion of cells in the Go/G1 phase and increases the proportion of cells in the S-phase, indicating a possible S-phase cell cycle arrest. These differences are also more significant in the cell lines with augmented sensitivity to the AKT-1 inhibitor. Therefore, altered cell cycle progression could be the major driver of the therapeutic benefits of the AKT-1 inhibitor. Overall, our findings suggest that AKT-1 inhibition is significantly more effective at reducing NSCLC cell viability in-vitro compared to pan-AKT inhibition. Furthermore, cell lines with higher CDK2 and AKT-3 expression have marginally increased sensitivity to the AKT-1 inhibitor A-674563 compared to the pan-AKT inhibitor MK-2206. Future research will focus on understanding the mechanism of action of the AKT-1 inhibitor through combined western blot, AKT antibody array, flow cytometry, and confocal microscopy data. Additionally, we will investigate the toxicity of these inhibitors on normal human small airway epithelial cells (HSAECs) to ensure preferential activity against malignant over somatic cells. Citation Format: Paige M. Chorner, Roger A. Moorehead. Inhibition of AKT-1 for the treatment of human non-small cell lung cancer (NSCLC) in-vitro [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 151. doi:10.1158/1538-7445.AM2017-151
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) | 0,000 | 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 ».