2. Academic Validation
  3. 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

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

  • Sci Rep. 2024 Dec 28;14(1):31062. doi: 10.1038/s41598-024-82137-9.
Liushan Chen # 1 2 3 4,  Lingling Ye # 1 3,  Yuqi Liang # 1 2 5 4,  Wei Luo 1 2 5,  Qian Zuo 1 2 3 4,  Ping Huang 1 2 3,  Yuyu Hu 1 2 3,  Yan Dai 1 3,  Yingchao Wu 6 7 8 9,  Qianqian Guo 10 11,  Qianjun Chen 12 13 14 15
Affiliations

Affiliations

  • 1 Chinese Medicine Guangdong Laboratory, Hengqin, 519031, Guangdong, China.
  • 2 Breast Disease Clinical Transformation Team, The Second Affiliated Hospital of Guangzhou, University of Chinese Medicine, Guangzhou, 510120, Guangdong, China.
  • 3 Breast Department, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510120, Guangdong, China.
  • 4 Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Zhuhai, 519031, Guangdong, China.
  • 5 The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China.
  • 6 Chinese Medicine Guangdong Laboratory, Hengqin, 519031, Guangdong, China. yc1996@stu2020.jnu.edu.cn.
  • 7 Breast Disease Clinical Transformation Team, The Second Affiliated Hospital of Guangzhou, University of Chinese Medicine, Guangzhou, 510120, Guangdong, China. yc1996@stu2020.jnu.edu.cn.
  • 8 The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China. yc1996@stu2020.jnu.edu.cn.
  • 9 Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Zhuhai, 519031, Guangdong, China. yc1996@stu2020.jnu.edu.cn.
  • 10 Chinese Medicine Guangdong Laboratory, Hengqin, 519031, Guangdong, China. guoqianqian@gzucm.edu.cn.
  • 11 Breast Department, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510120, Guangdong, China. guoqianqian@gzucm.edu.cn.
  • 12 Chinese Medicine Guangdong Laboratory, Hengqin, 519031, Guangdong, China. cqj55@163.com.
  • 13 Breast Disease Clinical Transformation Team, The Second Affiliated Hospital of Guangzhou, University of Chinese Medicine, Guangzhou, 510120, Guangdong, China. cqj55@163.com.
  • 14 Breast Department, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510120, Guangdong, China. cqj55@163.com.
  • 15 Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Zhuhai, 519031, Guangdong, China. cqj55@163.com.
  • # Contributed equally.
PMID: 39730704 DOI: 10.1038/s41598-024-82137-9
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.

Keywords

CDK4/6 inhibitor; Endocrine therapy; HER2 mRNA stability; HR+/HER2-low; Hsa-miR-23a-5p; Neratinib.

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