Data from A Fusion Transcription Factor–Driven Cancer Progresses to a Fusion-Independent Relapse via Constitutive Activation of a Downstream Transcriptional Target
Bibliographic record
Abstract
<div>Abstract<p>Targeted monotherapies usually fail due to development of resistance by a subgroup of cells that evolve into recurrent tumors. Alveolar rhabdomyosarcoma is an aggressive myogenic soft-tissue cancer that is associated with a characteristic <i>PAX3-FOXO1</i> gene fusion encoding a novel fusion transcription factor. In our myoblast model of PAX3-FOXO1–induced rhabdomyosarcoma, deinduction of PAX3-FOXO1 simulates a targeted therapy that antagonizes the fusion oncoprotein. This simulated therapy results initially in regression of the primary tumors, but PAX3-FOXO1–independent recurrent tumors eventually form after a delay. We report here that upregulation of <i>FGF8</i>, a direct transcriptional target of PAX3-FOXO1, is a mechanism responsible for PAX3-FOXO1–independent tumor recurrence. As a transcriptional target of PAX3-FOXO1, FGF8 promoted oncogenic activity in PAX3-FOXO1–expressing primary tumors that developed in the myoblast system. In the recurrent tumors forming after PAX3-FOXO1 deinduction, FGF8 expression was necessary and sufficient to induce PAX3-FOXO1–independent tumor growth through an autocrine mechanism. FGF8 was also expressed in human PAX3-FOXO1–expressing rhabdomyosarcoma cell lines and contributed to proliferation and transformation. In a human rhabdomyosarcoma cell line with reduced PAX3-FOXO1 expression, FGF8 upregulation rescued oncogenicity and simulated recurrence after PAX3-FOXO1–targeted therapy. We propose that deregulated expression of a PAX3-FOXO1 transcriptional target can generate resistance to therapy directed against this oncogenic transcription factor and postulate that this resistance mechanism may ultimately be countered by therapeutic approaches that antagonize the corresponding downstream pathways.</p>Significance:<p>In a model of cancer initiated by a fusion transcription factor, constitutive activation of a downstream transcriptional target leads to fusion oncoprotein-independent recurrences, thereby highlighting a novel progression mechanism and therapeutic target.</p></div>
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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) | 0.001 | 0.001 |
| 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 | 0.001 | 0.001 |
| Research integrity | 0.001 | 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 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".