Cooperative Lethality of Polo-Like Kinases (PLK) and Aurora Kinases (AK) in Refractory Pediatric Leukemia
Bibliographic record
Abstract
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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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 | 0.000 |
| 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".