Open Access

ARTICLE

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

Juan Wu^1,2, Yue Wang³, Honglin Yan¹, Juanjuan Li², Chuntao Quan^4,*, Jingping Yuan^1,*, Shengrong Sun^2,*

1 Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, China
2 Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, China
3 Department of Oncology Medicine, Central People’s Hospital of Zhanjiang, Zhanjiang, China
4 Department of Pathology, Biobank, Shenzhen Second People’s Hospital, Shenzhen University, Shenzhen, China

* Corresponding Authors: Chuntao Quan. Email: ; Jingping Yuan. Email: ; Shengrong Sun. Email:

(This article belongs to the Special Issue: Advances in Cancer Therapeutics)

Oncology Research 2026, 34(8), 25 https://doi.org/10.32604/or.2026.081653

Received 06 March 2026; Accepted 22 June 2026; Issue published 16 July 2026

Abstract

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.

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Supplementary Material

Supplementary Material File

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