Characterizing functional DNA damage and response caused by the combination of CHK1 and WEE1 inhibitors in ovarian and breast cancer models
Bibliographic record
Abstract
BACKGROUND: We proposed to quantify reduction of functional DNA damage response (DDR) mechanisms caused by the combination of CHK1 and WEE1 inhibitors. METHODS: Survival of cells and tumor growth in-vitro and in-vivo caused by the combination of the CHK1 inhibitor SRA737 and the WEE1 inhibitor adavosertib was studied in OVCAR3 and MDA-MB 436 cells. Functional DNA damage was quantified using in vitro cell free DNA assays. RESULTS: The combination of SRA737 and adavosertib caused significant reduction of survival of cells and DNA damage in-vitro and growth inhibition in-vivo. Studies using functional DDR assays found significant changes in the functional capacity of OVCAR3 but not MDA-MB 436 cells to repair DNA damage using multiple mechanisms including intra strand cross link repair, nucleotide excision repair, homologous recombination and non-homologous end joining. This study, for the first time provides a mechanistic insight into differences in the reduction in functional capacity of cells to repair DNA when exposed to CHK1 and WEE1 inhibitors. CONCLUSION: The combination of the CHK1 inhibitor SRA737 and WEE1 inhibitor adavosertib causes growth inhibition in-vitro and in-vivo, but differential functional inhibition of DDR in the models studied.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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".