Acquired resistance to CDK4/6 inhibition is associated with dysregulation of multiple pathways including cyclin D-CDK4/6-RB, EGFR/HER, AKT/mTOR and IFN signaling
Bibliographic record
Abstract
Abstract While the use of CDK4/6 inhibitors has significantly improved outcomes for patients with ER+/HER2- tumours, understanding the mechanisms responsible for resistance is essential to identify predictive biomarkers and alternative treatment options after tumour progression. To this end, we developed in-vitro models of acquired resistance to palbociclib and abemaciclib using MCF7 and T47D cell lines. Genomic, transcriptomic, and proteomic analyses were used to identify potential actionable molecular alterations in these models. Results show that acquired resistance was associated with dysregulation of multiple signaling pathways, including cyclin D-CDK4/6-RB, EGFR/HER and AKT/mTORC1. Strikingly, acquired resistance across all cell lines was also associated with an upregulated interferon (IFN) response. Expression of an IFN-based gene signature derived from these models was upregulated in breast cancer cell lines and early-stage tumours intrinsically resistant to CDK4/6i, and thus warrants further clinical evaluation as a predictive biomarker of resistance.
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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 | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| 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".