The tumor suppressor DACT3 sensitizes triple-negative breast cancer to apatinib by inhibiting the Wnt/β-catenin pathway.

Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2), shows efficient antitumor activity in heavily pretreated metastatic triple-negative breast cancer (TNBC). However, not all patients respond to apatinib, indicating that it is necessary to identify response biomarkers for more precise treatment and investigate the underlying mechanisms of apatinib resistance to develop new treatment strategies for TNBC. In this study, we identified the disheveled binding antagonist of beta-catenin 3 (DACT3) as a biomarker for apatinib sensitivity, as its expression level is significantly higher in apatinib-sensitive patients and positively correlates with longer survival. Furthermore, we explored that the exogenous expression of DACT3 could downregulate the IC(50) of apatinib (Vector vs DACT3: 16.04 μM vs 8.81 μM in MDA-MB231 cells, 19.65 μM vs 9.42 μM in YCCB1 cells) by inhibiting the Wnt/β-catenin signaling, a pro-malignancy pathway that leads to apatinib resistance through crosstalk with the VEGF/VEGFR2 pathway. In summary, our results indicate that DACT3 is a potential biomarker for predicting the response to apatinib and a new therapeutic target for improving TNBC sensitivity to apatinib.