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.

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.

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.

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.

The purpose of this study was to explore independent favorable prognostic factors for predicting 1-, 3-, and 5-year overall survival (OS) and cancer-specific survival (CSS) in patients with stage Ⅳ cell renal cell carcinoma (RCC) by constructing nomograms.

A total of 2636 patients diagnosed with stage Ⅳ RCC from 2010 to 2015 were enrolled in the surveillance, epidemiology, and end results database. Multivariate Cox hazard regression and competing risk analysis were used for searching prognosis factors in the cohort. The nomograms were constructed for predicting 1-, 3-, and 5-year of OS and CSS. Concordance index (C-index) and the calibration curves were used to evaluate the discrimination and accuracy of the nomograms.

Age, nephrectomy, histology, N stage, and brain/liver/lung metastasis were identified as independent favorable prognostic factors in OS and CSS via univariate and multivariate analyses. Other variables were further selected by clinical practice and net reclassification improvement (NRI). Finally, age, nephrectomy, histology, grade, tumor size, T stage, N stage, and bone/brain/liver/lung metastasis were chosen to construct nomograms. The C-index of the OS and CSS in nomograms were 0.697 (95% confidence interval (CI), 0.683–0.711) and 0.655 (95% CI, 0.639–0.671), respectively. The calibration curves revealed high consistency between the nomograms prediction and actual observation.

The nomograms may help clinicians to conveniently predict the survival of RCC patients with stage Ⅳ and provide guidance in choosing the suitable management.