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Overexpressed Cyclin D1 and CDK4 proteins are responsible for the resistance to CDK4/6 inhibitor in breast cancer that can be reversed by PI3K/mTOR inhibitors

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Abstract

CDK4/6 inhibitors are the standard treatment in advanced HR+/HER2− breast cancer patients. Nevertheless, the resistance to CDK4/6 inhibitors is inevitable and the strategies to overcome resistance are of great interest. Here, we show that the palbociclib-resistant breast cancer cells expressed significantly higher levels of Cyclin D1 and CDK4 proteins because of upregulated protein synthesis. Silencing Cyclin D1 or CDK4 led to cell cycle arrest while silencing Cyclin E1 or CDK2 restored the sensitivity to palbociclib. Furthermore, PI3K/mTOR pathway was hyper-activated in palbociclib-resistant cells, leading to more phosphorylated 4E-BP1 and higher levels of Cyclin D1 and CDK4 translation. Targeting PI3K/mTOR pathway with a specific PI3Kα inhibitor (BYL719) or an mTOR inhibitor (everolimus) reduced the protein levels of Cyclin D1 and CDK4, and restored the sensitivity to palbociclib. The tumor samples expressed significantly higher levels of Cyclin D1, CDK4, p-AKT and p-4E-BP1 after progression on palbociclib treatment. In conclusion, our findings suggest that overexpressed Cyclin D1 and CDK4 proteins lead to the resistance to CDK4/6 inhibitor and PI3K/mTOR inhibitors are able to restore the sensitivity to CDK4/6 inhibitors, which provides the biomarker and rationale for the combinational use of CDK4/6 inhibitors and PI3K/mTOR inhibitors after CDK4/6 inhibitor resistance in breast cancer.

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Acknowledgements

This work was supported by the Notional Natural Science Foundation of China (82061148016, 81630074, 81872141, 81702630, 81672622), Guangzhou Science and Technology Plan Key Projects (201804020076), and Natural Science Foundation of Guangdong (2019A1515010146), and Beijing Medical Award Foundation (YXJL-2020-0941-0760), and China Postdoctoral Science Foundation (2021TQ0384, 2021M703731).

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Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China

    Zijie Cai, Jingru Wang, Yudong Li, Qianfeng Shi, Liang Jin, Shunying Li, Mengdi Zhu, Qi Wang, Lok Lam Wong, Wang Yang, Hongna Lai, Chang Gong, Yandan Yao, Yujie Liu, Herui Yao & Qiang Liu

  2. Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China

    Zijie Cai, Jingru Wang, Yudong Li, Qianfeng Shi, Liang Jin, Shunying Li, Mengdi Zhu, Qi Wang, Lok Lam Wong, Wang Yang, Hongna Lai, Chang Gong, Yandan Yao, Yujie Liu, Herui Yao & Qiang Liu

  3. Department of Thyroid and Breast Surgery, Shenzhen Nanshan District Shekou People’s Hospital, Shenzhen, 518067, China

    Jun Zhang

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  1. Zijie Cai
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Cai, Z., Wang, J., Li, Y. et al. Overexpressed Cyclin D1 and CDK4 proteins are responsible for the resistance to CDK4/6 inhibitor in breast cancer that can be reversed by PI3K/mTOR inhibitors. Sci. China Life Sci. 66, 94–109 (2023). https://doi.org/10.1007/s11427-021-2140-8

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