Ruthenium Drug BOLD-100 Regulates <i>BRAF</i> MT Colorectal Cancer Cell Apoptosis through AhR/ROS/ATR Signaling Axis Modulation
Bibliographic record
Abstract
Patients with class I V600EBRAF-mutant (MT) colorectal cancer exhibit a poor prognosis, and their response to combined anti-BRAF/EGFR inhibition remains limited. An unmet need exits for further understanding the biology of V600EBRAFMT colorectal cancer. We used differential gene expression of BRAFWT and MT colorectal cancer cells to identify pathways underpinning BRAFMT colorectal cancer. We tested a panel of molecularly/genetically subtyped colorectal cancer cells for their sensitivity to the unfolded protein response (UPR) activator BOLD-100. To identify novel combination strategies for BOLD-100, we performed RNA sequencing and high-throughput drug screening. Pathway enrichment analysis identified significant enrichment of the UPR and DNA repair pathways in BRAFMT colorectal cancer. We found that oncogenic BRAF plays a crucial role in mediating the response to BOLD-100. Using a systems biology approach, we identified V600EBRAFMT-dependent activation of the replication stress response kinase ataxia telangiectasia and Rad3-related (ATR) as a key mediator of resistance to BOLD-100. Further analysis identified acute increases in BRAFMT-dependent-reactive oxygen species levels following treatment with BOLD-100, which promoted ATR/CHK1 activation and apoptosis. Furthermore, activation of reactive oxygen species/ATR/CHK1 following BOLD-100 was mediated through the AhR transcription factor and CYP1A1. Importantly, pharmacological blockade of this resistance pathway with ATR inhibitors synergistically increased BOLD-100-induced apoptosis and growth inhibition in BRAFMT models. These results highlight a possible novel therapeutic opportunity for BRAFMT colorectal cancer. Implications: BOLD-100 induces BRAFMT-dependent replication stress, and targeted strategies against replication stress (e.g., by using ATR inhibitors) in combination with BOLD-100 may serve as a potential novel therapeutic strategy for clinically aggressive BRAFMT colorectal 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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".