biostudies-literatureChen LScience and Technology Innovation Medical Development Foundation of BeijingBasic and Applied Basic Research Foundation of Guangdong ProvinceNational Natural Science Foundation of ChinaProject supported by the Incubation Program for the Science and Technology Development of Chinese Medicine Guangdong Laboratory31062https://www.ebi.ac.uk/biostudies/studies/S-EPMC11680982biostudies-literatureUnknown14(1)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.Scientific reportsNeratinib enhances the efficacy of CDK4/6 inhibitor plus endocrine therapy in HR<sup>+</sup>/HER2-low breast cancer cell line ZR-75-1 via hsa-miR-23a-5p.PMC11680982KC2021-ZZ-0010-92022A1515110859KC2022-ZZ-0091-182274513HQL2024PZ023Ye LChen QHu YLiang YChen LLuo WGuo QZuo QDai YWu YHuang PfalseNeratinib enhances the efficacy of CDK4/6 inhibitor plus endocrine therapy in HR<sup>+</sup>/HER2-low breast cancer cell line ZR-75-1 via hsa-miR-23a-5p.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.2024-01-01T00:00:00Z2024 Dec2025-04-04T02:36:43.799Z2025-04-04T02:36:43.799ZS-EPMC116809823973070410.1038/s41598-024-82137-9