1. Neratinib enhances the efficacy of CDK4/6 inhibitor plus endocrine therapy in HR + /HER2-low breast cancer cell line ZR-75-1 via hsa-miR-23a-5p.
- Author
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Chen L, Ye L, Liang Y, Luo W, Zuo Q, Huang P, Hu Y, Dai Y, Wu Y, Guo Q, and Chen Q
- Subjects
- Humans, Female, Cell Line, Tumor, Animals, Mice, Gene Expression Regulation, Neoplastic drug effects, Protein Kinase Inhibitors pharmacology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Xenograft Model Antitumor Assays, Drug Synergism, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, MicroRNAs genetics, MicroRNAs metabolism, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Breast Neoplasms genetics, Breast Neoplasms pathology, Cyclin-Dependent Kinase 6 antagonists & inhibitors, Cyclin-Dependent Kinase 6 metabolism, Cyclin-Dependent Kinase 6 genetics, Cyclin-Dependent Kinase 4 antagonists & inhibitors, Cyclin-Dependent Kinase 4 metabolism, Cyclin-Dependent Kinase 4 genetics, Receptor, ErbB-2 metabolism, Receptor, ErbB-2 genetics, Receptor, ErbB-2 antagonists & inhibitors, Quinolines pharmacology
- Abstract
HR
+ /HER2-low breast cancer is a significant subgroup of conventional HR+ /HER2-negative breast cancer, and combination of CDK4/6 inhibitor and endocrine therapy is the standard first-line and second-line treatments for advanced HR+ /HER2-low breast cancer. Nevertheless, it remains uncertain whether HER2 signaling affects the effectiveness of CDK4/6 inhibitor administered in combination with endocrine therapy for HR+ /HER2-low breast cancer and suitable intervention measures. This study revealed poor efficacy for CDK4/6 inhibitor combined with endocrine therapy for HR+ /HER2-low breast cancer in vitro and in vivo models. Secondly, suppression of HER2 gene expression in HR+ /HER2-low breast cancer cells resulted in significantly improved efficacy for CDK4/6 inhibitor combined with endocrine therapy. Furthermore, the anti-HER inhibitor neratinib was administered to enhance the effectiveness of CDK4/6 inhibitor combined with endocrine therapy in HR+ /HER2-low breast cancer by inhibiting the HER2 pathway and lowering HER2 mRNA expression. Strikingly, neratinib reversed the efficacy of CDK4/6 inhibitor and endocrine therapy by reducing HER2 mRNA stability in HR+ /HER2-low breast cancer through the interaction of HER2 3'-UTR region with hsa-miR-23a-5p. Even after reducing neratinib dosage to the standard 1/2 dose (20 mg/kg), it remained highly effective and well-tolerated. This study provides a viable and well-tolerated triple combination therapy for clinical HR+ /HER2-low breast cancer., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: This study was conducted according to ARRIVE guidelines 2.0. Liushan Chen, Lingling Ye, and Yuqi Liang are co-first authors. Yingchao Wu, Qianqian Guo, and Qianjun Chen are co-corresponding authors., (© 2024. The Author(s).)- Published
- 2024
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