Focal Adhesion Kinase Intersects With the BRD4‐MYC Axis and YAP1 to Drive Tumor Cell Growth, Phenotypic Plasticity, Stemness, and Metastatic Potential in Colorectal Cancer
Bibliographic record
Abstract
OBJECTIVE: Colorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide due to the lack of effective therapies. Here we explored the clinical basis and therapeutic promise of the integrin-focal adhesion kinase (FAK)-dependent pathway for CRC. METHODS AND RESULTS: phosphorylation) increased by threefold from stage I to III/IV tumors or metastatic lesions. Consistent with this clinic landscape, FAK inhibition via knockdown or chemical inhibitors suppressed tumor cell growth largely in the subset of CRC cell lines with low MYC expression. In contrast, the FAK inhibition was less effective in the cell line pool with high MYC expression. The resistance to FAK targeting diminished upon a co-inhibition of BRD4 via BET inhibitors. It coincided with an induction of cell cycle arrest at G1-S and G2-M phases, elevated apoptosis and chemosensitivity (paclitaxel and oxaliplatin), and impaired stemness. Mechanistically, the BET inhibitor induced an EMT-like phenotype, tilting tumor cell dependence toward the integrin-FAK axis. Moreover, inhibiting FAK alone or in combination with SRC or BRD4 markedly suppressed cell motility and the YAP or MYC activation, and restored the expression of the long isoform BRD4. Also, co-genomic/genetic dysregulations of FAK and YAP1 or SRC strongly correlated with poor disease-free patient survival. CONCLUSION: Overall, our study highlights the potent pro-malignant role of the integrin-FAK axis in CRC, fueling its targeting as a single agent or synthetic lethal-based therapy.
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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".