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Alternative Splicing in Cyclin-Dependent Kinase 4/6 Inhibitor Resistance in Estrogen Receptor-Positive Breast Cancer
Yuqiu Cui1,2, Jia Xie1,2, Jiale Cai1,2
1School of Medicine (Institute of Translational Medicine), Yangzhou University, Yangzhou, China.
Drug Development Research
|August 10, 2026
Summary
Alternative splicing, a key process in gene expression, drives resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in estrogen receptor-positive (ER+) breast cancer, offering new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Estrogen receptor-positive (ER+) breast cancer is a major cause of cancer deaths in women.
- Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are vital treatments for ER+ breast cancer.
- Drug resistance to CDK4/6i is a significant clinical challenge.
Purpose of the Study:
- To review the molecular mechanisms of CDK4/6i resistance in ER+ breast cancer.
- To highlight the role of alternative splicing in mediating this resistance.
- To explore potential therapeutic strategies targeting splicing dysregulation.
Main Methods:
- Comprehensive literature analysis of CDK4/6i resistance mechanisms.
- Focus on alternative splicing as a post-transcriptional regulatory mechanism.
- Examination of signaling pathways involved in resistance.
Main Results:
- Alternative splicing dysregulation contributes to resistance via cell-cycle control, epithelial-mesenchymal transition, and signaling pathways.
- Reduced NSRP1 expression may link to resistance through altered NSD2 splicing and interferon signaling.
- Splicing dysregulation impacts multiple pathways crucial for tumor growth and drug response.
Conclusions:
- Alternative splicing is a critical, evolving area in understanding and overcoming CDK4/6i resistance.
- Targeting splicing events presents a promising avenue for novel therapeutic development.
- Combining CDK4/6i with splicing modulators may reverse or delay resistance.