Cooperative Lethality of Polo-Like Kinases (PLK) and Aurora Kinases (AK) in Refractory Pediatric Leukemia
Notice bibliographique
Résumé
Abstract Abstract 3573 Introduction: Recent studies have shown that cell cycle events are tightly controlled by complex and shared activities of a select group of kinases. Among these, Polo like kinases (Plk) are regulatory mitotic proteins that are overexpressed in several types of cancer and are associated with poor prognosis. Consequently, inhibitors for these kinases are currently being evaluated as anticancer drugs in Phase I and Phase II clinical trials. However, details of the mechanisms by which the interference of selective regulators of mitosis lead to cell death is currently unavailable. We describe experimental studies to further understand this process and to investigate the activity, drug combinability and target modulation of Plk inhibition in refractory pediatric leukemia cells. Methods: Cell lines derived from relapsed pediatric leukemia patients were used (n=12). These cells carry the spectrum of moleular abnormalites found in patients including MLL gene rearrangemnet with various fusion genes (Bcr-Abl), and biphenotypic features. Leukemia cells were incubated with increasing concentrations of the Plk1 inhibitor volasertib (BI 6727, Boehringer Ingelheim) and after four days in culture, cell growth characteristics including cellular morphology, ploidy status and cell survival were quantified by automated quantitative microscopy. IC50 values and combination indices were calculated according to the method of Chou and Talalay. Activities of intracellular signaling components and regulators of distinct apoptosis and autophagy pathways were identified by Western blot analysis. Results: Volasertib inhibited the growth of all leukemia cell lines tested, as well as primary specimens from leukemia patients, at sub-micromolar concentrations (IC50 from 1 × 10−6 to 1 μM). Microscopic and ultrastructural analyses revealed a corresponding increase in the number of cells displaying abnormal phenotype and mitotic catastrophe, a characteristic of Plk inhibition. Plk inhibition also resulted in an initial upregulation of Aurora-A and Aurora-B expression and the phosphorylation of Aurora-B and Aurora-C. However, sustained Plk inhibition led to time dependent dephosphorylation of Aurora-A. In addition, Plk inhibition resulted in Caspase-9 cleavage and decreased expression of autophagy related proteins (Atg3). Overall, significant synergy was observed when AK inhibitors were combined with Plk inhibition (CI = 0.02 – 0.8). Conclusions: We provide experimental data to show that Plk1 inhibition by volasertib significantly decreases the growth and survival of refractory pediatric leukemia cells in vitro. We also show synergy between AK and Plk inhibition in leukemia cells and that an effective target modulation by Plk inhibition leads to alterations in intracellular AKs in a time dependent manner. Our data provide relevant information regarding the relationship between the two kinases and the intracellular changes that can be used as biological correlates for therapeutic activity in future clinical studies. These findings provide initial pre-clinical evidence for Plk as a potentially effective target in pediatric leukemia therapy. Disclosures: No relevant conflicts of interest to declare.
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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) | 0,001 | 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 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 ».