Inhibition of EphA2 receptor tyrosine kinase activity by dasatinib in pancreatic cancer.
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".