Novel macromolecule CPD4 suppresses cell proliferation and metastasis of triple-negative breast cancer by targeting ROR1 protein

Abstract

Breast cancer is the second most common cancer among women in the US, with triple-negative breast cancer (TNBC) accounting for 15–20 % of new diagnoses. TNBC cells lack estrogen and progesterone receptors, and human epidermal growth factor receptor 2, which makes them resistant to standard hormone treatments. Current therapies like chemotherapy and radiation often harm both cancerous and healthy cells, underscoring the need for developing new targeted treatments. ROR1, an oncoprotein that is overexpressed in various cancers, including breast cancer, is minimally present in normal tissues. Targeting ROR1 signaling has been shown to trigger apoptosis and reduce TNBC cell proliferation. A novel macromolecule compound, CPD4, was discovered through in-silico docking for its ability to bind and inhibit the pseudokinase domain of ROR1. In vitro evidence revealed that CPD4 decreases cell viability and induces apoptosis in TNBC cell lines at concentrations of 2–10 μM, while leaving normal breast cells unharmed. CPD4 also blocks migration, invasion, and causes G2/M-phase arrest in TNBC cells. Its mechanism of action involves reducing key downstream markers of ROR1 signaling, particularly the phosphorylation of AKT/GSK3β. In 3D spheroid cultures, CPD4 reduces the size of TNBC spheroids. Moreover, the combination treatment of CPD4 and the standard chemotherapy docetaxel exhibits synergistic efficacy against different TNBC cell lines with a combination index below 0.01. These results suggest that CPD4 holds promise as a therapeutic option for TNBC and could potentially benefit other cancers with ROR1 overexpression.