P36 - Adavosertib-mediated wee1 inhibition as a strategy to overcome cisplatin resistance in non-seminoma testicular cancer: insights from preclinical models
Bibliographic record
Abstract
Abstract Background/Introduction Testicular germ cell tumors (TGCTs) are the most common solid malignancy in young adult males with non-seminomatous representing a clinically aggressive subtype. Although cisplatin (CP)-based chemotherapy is highly effective, with cure rates exceeding 95%, a subset of patients develop resistance. The identification of therapeutic strategies to overcome CP-resistance remains an urgent clinical need. Purpose In this study, we evaluated the expression and pharmacological targeting of WEE1, a key regulator of the G2/M checkpoint and replication stress response, in non- seminoma cell models using the WEE1 inhibitor adavosertib (AZD1775). Methods Two non-seminoma cell lines, NCCIT and NT2/D1, and their CP-resistant subclones (NCCIT-R and NT2/D1-R) were used. The effects of adavosertib and CP, alone or in combination, on cell viability, cell-cycle progression, apoptosis, and DNA damage markers was assessed. Results WEE1 was expressed in non-seminoma cell models. Adavosertib reduced cell viability in a dose-dependent manner across all cell models in both 2D and 3D cultures. IC50 values were consistently in the low micromolar range with minimal variation (NCCIT: 0.550 μM; NCCIT-R: 0.630 μM; NT2/D1: 0.415 μM; NT2/D1-R: 0.630 μM). Adavosertib altered cell-cycle distribution, increasing S-phase population. Western blot analysis showed reduced CDK1 phosphorylation, indicating elevated CDK1 activity, with increased H3 phosphorylation, a mitotic marker. These findings suggest WEE1 inhibition disrupts cell cycle checkpoints, promotes replication stress, and drives cells with unrepaired DNA damage into premature mitosis, resulting in mitotic catastrophe. Caspase 3/7 activity was also increased after treatment, specifically at 24 hours, together with elevated markers of DNA damage (pH2Ax) and apoptosis (cleaved-PARP and cleaved-Caspase 3). In combination treatments, adavosertib enhanced CP efficacy across all models, including resistant lines. Notably, in NCCIT-R cells, CP IC50 dropped from 11.65 to 1.99 μM when combined with adavosertib, indicating a sixfold increase in CP-sensitivity. Conclusion(s) Overall, our findings demonstrate that WEE1 is expressed in non- seminoma models and is targetable. Pharmacological inhibition of WEE1 by adavosertib impairs cell viability, disrupts cell-cycle control, induces apoptosis, and restores CP-sensitivity in resistant models. These results provide compelling preclinical evidence supporting the combination of WEE1 inhibition with standard chemotherapy as a promising strategy to overcome CP-resistance in non-seminoma testicular cancer.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| 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) | 0.000 | 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 teacher head, 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".