@article{Wu2026, 
author = {Juan Wu and Yue Wang and Honglin Yan and Juanjuan Li and Chuntao Quan and Jingping Yuan and Shengrong Sun},
title = {Targeting Aurora A Kinase Enhance the CDK4/6 Inhibitor Sensitivity in HR+/HER2- Breast Cancer},
year = {2026},
journal = {Oncology Research},
volume = {34},
number = {8},
pages = {25},
keywords = {CDK4/6i resistance, spindle assembly checkpoint, Aurora A kinase, RB phosphorylation, ubiquitination},
url = {https://www.sciopen.com/article/10.32604/or.2026.081653},
doi = {10.32604/or.2026.081653},
abstract = {ObjectivesDespite the success of CDK4/6 inhibitors (CDK4/6i) in treating HR+/HER2- breast cancer (BC), some patients experience treatment failure due to CDK4/6i resistance. This study aimed to investigate whether targeting Aurora A kinase enhances CDK4/6 inhibitor sensitivity.MethodsAn Abemaciclib-resistant cell line (MCF7AR) was developed by treating MCF7 cells with gradually increasing concentrations of Abemaciclib. We evaluated the relative protein levels of p-RB, p-Aurora A, Aurora A, and USP22 in cell cultures, animal tissues, and clinical samples. The effect of Aurora A inhibition on reversing CDK4/6i resistance was assessed using cell viability assays and tumor xenograft experiments. We examined the relationship between Aurora A kinase activation levels and resistance to CDK4/6i.ResultsCDK4/6i-resistant cell lines and patient samples exhibited elevated levels of phosphorylated Aurora A and retinoblastoma protein (RB). Previous studies have reported that RB inactivation can activate the spindle assembly checkpoint (SAC), leading to mitotic delay. High Aurora A activity counteracts the SAC-induced delay, thereby promoting mitosis. CDK4/6i treatment increased Aurora A protein levels through regulation by USP22, enhancing Aurora A activity and overcoming SAC-mediated cell cycle arrest. Combined therapy with Aurora A inhibitor (Aurora Ai) and CDK4/6i demonstrated synergistic antitumor effects both in vitro and in vivo. Clinical data suggest that HR+/HER2- patients with high levels of phosphorylated RB and Aurora A may exhibit resistance to CDK4/6i.ConclusionAurora A contributes to CDK4/6i resistance by overcoming SAC delay and promoting mitosis. In RB-inactivated CDK4/6i-resistant cells, Aurora A inhibition may induce a synthetic lethal effect.}
}