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Single-cell transcriptomics reveals biomarker heterogeneity linked to CDK4/6 Inhibitor resistance in breast cancer
Ilenia Migliaccio1, Martina Bonechi1, Dario Romagnoli2,3
1Translational Research Unit, Department of Oncology, Hospital of Prato, Azienda USL Toscana Centro, Prato, Italy.
Abstract:
Cyclin dependent kinases 4 and 6 inhibitors have brought great improvements in the treatment of luminal breast cancer, but resistance is a major clinical hurdle. Multiple biomarkers of resistance have been proposed, but none is currently utilized in clinical practice. By performing single-cell RNA sequencing of seven palbociclib-naïve luminal breast cancer cell lines and palbociclib-resistant derivatives, we show that established biomarkers and pathways related to CDK4/6i resistance present marked intra- and inter- cell-line heterogeneity. Transcriptional features of resistance could be already observed in naïve cells correlating with levels of sensitivity (IC50) to palbociclib. Resistant derivatives showed transcriptional clusters that significantly varied for proliferative, estrogen response signatures or MYC targets. This marked heterogeneity was validated in the FELINE trial where, compared to the sensitive ones, ribociclib-resistant tumors developed higher clonal diversity at genetic level and showed greater trascriptional variability for genes associated with resistance. A potential signature of resistance inferred from the cell-line models, positively enriched for MYC targets and negatively enriched for estrogen response markers, was probed on the FELINE trial, separating sensitive from resistant tumors and revealing higher heterogeneity in resistant versus sensitive cells. These data suggest that heterogeneity for CDK4/6 inhibitors resistant markers might facilitate the development of resistance and challenge the validation of clinical biomarkers.
Insights
Resistance to cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) in breast cancer is a challenge. Our study reveals significant heterogeneity in resistance markers, impacting treatment strategies and biomarker validation.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) are effective in luminal breast cancer.
- Therapeutic resistance to CDK4/6i remains a significant clinical challenge.
- Current biomarkers for CDK4/6i resistance lack clinical utility.
Purpose of the Study:
- To investigate the heterogeneity of resistance mechanisms to CDK4/6 inhibitors in luminal breast cancer.
- To identify potential transcriptional biomarkers associated with CDK4/6i resistance.
- To validate findings from cell line models in a clinical trial setting.
Main Methods:
- Single-cell RNA sequencing was performed on palbociclib-naïve and resistant luminal breast cancer cell lines.
- Transcriptional profiles were analyzed for heterogeneity and correlation with drug sensitivity.
- Resistance signatures were validated using data from the FELINE clinical trial.
Main Results:
- Marked intra- and inter-cell-line heterogeneity was observed for established CDK4/6i resistance biomarkers and pathways.
- Transcriptional features of resistance were present in naïve cells and correlated with sensitivity.
- Resistant cell lines and tumors exhibited distinct transcriptional clusters, including variations in proliferative, estrogen response, and MYC target signatures.
- A resistance signature enriched for MYC targets and depleted of estrogen response markers differentiated sensitive from resistant tumors in the FELINE trial, with greater heterogeneity in resistant cases.
Conclusions:
- Heterogeneity in CDK4/6 inhibitor resistance markers may drive treatment failure.
- The observed heterogeneity challenges the clinical validation of single biomarkers for CDK4/6i resistance.
- Further research is needed to understand and target resistance mechanisms in luminal breast cancer.
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