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 machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".