Development of an organoid-based pan-TKI precision screening platform to enhance therapeutic efficacy of ET+CDK4/6 inhibitors in HR+/HER2-low breast cancer
WU Yingchao
CHEN Liushan
LIANG Yuqi
CHEN Jieting
HUANG Junfeng
ZUO Qian
CHEN Qianjun
Abstract：Objective To investigate the underlying mechanisms contributing to the limited therapeutic efficacy of endocrine therapy combined with CDK4/6 inhibitors in HR+/HER2-low breast cancer,and to develop a breast cancer organoid model as a tool for the precise identification of HR+/HER2-low patients who are responsive to pan-TKI treatment.Methods Transcriptomics was employed to identify differentially expressed genes in HR+/HER2-0 and HR+/HER2-low breast cancer samples and to perform functional enrichment analysis.Tumor organoid models were established using breast cancer tissues obtained from clinical sources,and the differential sensitivity of these samples to therapeutic agents was assessed using Calcein-AM/PI cell viability staining and EdU-based cell proliferation assays.Results The results of transcriptomic enrichment analysis indicated that EGFR was signifi-cantly activated in HR+/HER2-low breast cancer and exhibited characteristics of resistance to TKIs.Breast cancer organoids were successfully established.Drug sensitivity testing revealed that the therapeutic efficacy of ET combined with CDK4/6 inhibitors was suboptimal in certain cases of HR+/HER2-low breast cancer,while the addition of TKIs effectively restored sensitivity to the ET+CDK4/6 inhibitor regimen(P<0.05).Conclusions TKI can restore the reduced sensitivity of HR+/HER2-low breast cancer to endocrine therapy combined with CDK4/6 inhibitors.Breast cancer organoids hold promise as screening tools for assessing drug sensitivity in clinical settings for patients with HR+/HER2-low breast cancer.
Keywords：breast cancerHR+/HER2-lowET+CDK4/6 inhibitororganoidtyrosine kinase in-hibitor
Publication Date：2025-09-25
Online Publishing Date：2025-09-30(First online date of this platform, not the publication date of the document)
Pages：10( 2786-2795 )