LncRNA EILA promotes CDK4/6 inhibitor resistance in breast cancer by stabilizing cyclin E1 protein

CDK4/6 inhibitors (CDK4/6i) plus endocrine therapy are now standard first-line therapy for advanced HR+/HER2- breast cancer, but developing resistance is just a matter of time in these patients. Here, we report that a cyclin E1-interacting lncRNA (EILA) is up-regulated in CDK4/6i-resistant breast cancer cells and contributes to CDK4/6i resistance by stabilizing cyclin E1 protein. EILA overexpression correlates with accelerated cell cycle progression and poor prognosis in breast cancer. Silencing EILA reduces cyclin E1 protein and restores CDK4/6i sensitivity both in vitro and in vivo. Mechanistically, hairpin A of EILA binds to the carboxyl terminus of cyclin E1 protein and hinders its binding to FBXW7, thereby blocking its ubiquitination and degradation. EILA is transcriptionally regulated by CTCF/CDK8/TFII-I complexes and can be inhibited by CDK8 inhibitors. This study unveils the role of EILA in regulating cyclin E1 stability and CDK4/6i resistance, which may serve as a biomarker to predict therapy response and a potential therapeutic target to overcome resistance.

Automated summary

This study reveals that a long non-coding RNA (EILA) that interacts with cyclin E1 is up-regulated in CDK4/6 inhibitor-resistant breast cancer cells and contributes to resistance by stabilizing cyclin E1 protein. EILA overexpression is associated with accelerated cell cycle progression and poor prognosis in breast cancer. Silencing EILA reduces cyclin E1 protein and restores sensitivity to CDK4/6 inhibitors both in vitro and in vivo.