Alternative Splicing in Cyclin-Dependent Kinase 4/6 Inhibitor Resistance in Estrogen Receptor-Positive Breast Cancer

Breast cancer is one of the leading causes of cancer-related deaths among women worldwide, with estrogen receptor-positive (ER+) breast cancer being the most common subtype. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have become a crucial therapeutic approach for this type of cancer. However, ER+ breast cancer frequently develops resistance to CDK4/6i, limiting therapeutic efficacy. Alternative splicing is a key post-transcriptional regulatory mechanism that may drive such resistance. In this review, we comprehensively analyzed the literature on the molecular mechanisms and key signaling pathways associated with CDK4/6i resistance in ER+ breast cancer and introduced the role of alternative splicing, with a particular focus on its function in tumor drug resistance. Available evidence suggests that splicing dysregulation may influence resistance through multiple pathways, including cell-cycle control, epithelial-mesenchymal transition, growth factor and RAS/MAPK signaling, and immune-related programs. Recent work has also suggested that reduced expression of the splicing regulator NSRP1 may be associated with CDK4/6i resistance through altered NSD2 splicing and activation of interferon signaling, although this mechanism currently requires further independent validation. Collectively, these findings support alternative splicing as a promising but still evolving area of investigation in CDK4/6i resistance. This work provides deeper insights into the role of alternative splicing in CDK4/6i resistance and offers a theoretical foundation for developing novel therapeutic approaches. Future research may focus on developing drugs that precisely modulate specific splicing events or combining CDK4/6i with splicing modulators to reverse or delay resistance.