Targeting Aurora A Kinase Enhance the CDK4/6 Inhibitor Sensitivity in HR+/HER2-Breast CancerOA

Objectives:Despite 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.Methods:An 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.Results:CDK4/6i-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.Conclusion:Aurora 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.