Abstract PD2-10: Predicting sensitivity to CDK4/6 inhibition in ER+/HER2- breast cancer cell lines
Bibliographic record
Abstract
Abstract Background: For treatment of metastatic or advanced ER+/HER2- breast cancer, CDK4/6 inhibition (CDKi), including CDK4/6 inhibitors palbociclib, ribociclib and abemaciclib, is now the standard of care. Approximately 25% of patients however will not respond or demonstrate progression within 6 months. The successful clinical implementation of these agents will require understanding which patient subgroups are more likely to benefit from targeted therapies. The goal of this study was to identify molecular alterations contributing to the intrinsic and acquired resistance to CDK4/6 inhibition. Methods/Results: A panel of fifteen ER+/HER2- cell lines was characterized using a NanoString PAM50-like assay as well as next generation sequencing. Cell lines were screened with three CDK4/6 inhibitors: palbociclib, ribociclib and abemaciclib. Growth rate (GR) inhibition metrics, which control for different doubling times of the cell lines, were used to generate normalized GR inhibition values. A range of sensitivities to palbociclib was observed based on molecular alterations, varying from 75 to 200nM in sensitive cell lines to 800nM to >5000nM in resistant cell lines. In response to 24h treatment with 1µM palbociclib, cell lines downregulated expression of E2F-target genes involved in cell cycle progression, and increased growth factor receptor signaling. Following treatment with 1µM palbociclib, resistant cell lines had increased expression of genes involved in DNA repair, replication and cell cycle checkpoints, as well as downregulation of genes involved in the regulation of cellular response to growth factor stimulation. Downregulated genes included several members of the DUSP family of phosphatases that are responsible for negative regulation of MAPK signaling, and infers a possible target population for treatment with palbociclib. To determine whether the same pathways driving intrinsic resistance to palbociclib are also driving acquired resistance, two in-vitro models of acquired resistance to CDKi were developed by treating MCF7 and T47D cell lines with increasing concentrations of palbociclib or abemaciclib. Loss of RB1 was observed in MCF7 CDKi-resistant cell lines, as well as copy number gains of EGFR, BRCA1 and SMO. In the MCF7 CDKi-resistant cell lines, increased activity of EGFR and MAPK signaling pathways as well as increased expression of cyclin E1 was observed. Conclusions: These results suggest that alterations in cell cycle and MAPK signaling pathways contribute to both intrinsic and acquired resistance to CDKi in ER+/HER2- breast cancer cell lines. Citation Format: Lauren Bathurst, Linda Liao, Cheryl Crozier, Jane Bayani, John Bartlett, Melanie Spears. Predicting sensitivity to CDK4/6 inhibition in ER+/HER2- breast cancer cell lines [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD2-10.
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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 | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".