Inhibition of EphA2 receptor tyrosine kinase activity by dasatinib in pancreatic cancer.
Notice bibliographique
Résumé
C174 Eph receptors constitute the largest family of receptor tyrosine kinases (RTKs) in the human genome. Their ligands, which fall into the ephrin A and ephrin B classes, are surface bound, and bidirectional ephrin receptor/ligand interactions play an important role in normal tissue development. Aberrant Eph receptor function is implicated in cellular transformation, metastasis, and angiogenesis. EphA2 is one prominent member that is over-expressed and functionally altered in many invasive cancers, including pancreatic cancer. Although the mechanisms by which EphA2 contributes to tumor cell malignancy are far from clear, it potentially represents a therapeutic target for novel anticancer agents. Dasatinib, which is a multi-targeted kinase inhibitor mainly developed for Bcr-Abl and Src family kinases, has recently been shown to have significant activity against EphA2 (Huang et al. Cancer Res 2007; 67: 2226-38). Since selective small molecule EphA2 inhibitors are not currently available, we investigated the therapeutic potential to target EphA2 by dasatinib in BxPC-3, PANC-1, and MIA PaCa-2 pancreatic cancer cell lines. Using an in vitro kinase assay, we found that EphA2 receptor tyrosine kinase was inhibited directly by dasatinib in a dose-dependent manner. In all three pancreatic cancer cell lines, low basal levels of EphA2 tyrosine phosphorylation were detected by immunoprecipitation. Stimulation with ephrinA1-Fc ligand produced rapid increases of EphA2 phosphorylation, associated with activation of Akt in all three cell lines. In BxPC-3, but not in PANC-1 or MIA PaCa-2 cells, we also observed increased Y705-STAT3, whereas PANC-1 and MIA PaCa-2 cells showed increased ERK phosphorylation and a transient loss of focal adhesion kinase phosphorylation following EphA2 activation. These results suggest that the effects of EphA2 activation on cell behavior differ among the pancreatic cancer cell lines. In addition to Src, dasatinib inhibited EphA2 tyrosine kinase activity as well as downstream effectors of EphA2 in pancreatic cancer cell lines. Furthermore, dasatinib caused G1 arrest, not seen with the well characterized Src inhibitor PP2 except at the highest concentration, suggesting that EphA2 receptor tyrosine kinase inhibition but not Src inhibition resulted in cell cycle arrest. Previous work has shown that ligand binding results in the internalization and proteasomal degradation of EphA2 (Walker-Daniels et al. Mol Cancer Res 2002; 1: 79-87). We observed that dasatinib inhibited ligand-induced internalization and degradation of EphA2, suggesting that this is dependent on kinase activity. Preliminary in vivo experiments showed that treatment with dasatinib results in a transient decrease of EphA2 phosphorylation in BxPC-3 xenografts, suggesting that this drug might have activity in pancreatic cancer due to EphA2 inhibition, in addition to its effects on Src. We conclude that EphA2 is a promising therapeutic target in pancreatic cancer, and that the development of more selective inhibitors for clinical testing is indicated.
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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 | 0,001 |
| 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 ».