Novel strategies to target chemoresistant triple-negative breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Current treatments for triple-negative breast cancer (TNBC) eliminate most tumor cells but spare cancer stem cells (CSCs), leading to resistance and recurrence.
• Cancer stem cells (CSCs) are implicated in chemotherapy resistance and tumor regrowth in TNBC.
• The FZD8-mediated Wnt signaling pathway is a potential therapeutic target in TNBC.

Purpose of the Study:

• To investigate the efficacy of CFM-4.16 (CARP-1 functional mimetic) in combination with cisplatin against TNBC.
• To determine the effect of this combination therapy on cancer stem cells (CSCs) and chemoresistance.
• To explore the role of FZD8-mediated Wnt signaling in TNBC chemoresistance.

Main Methods:

• Treatment of TNBC cell lines (MDA-MB-468, MDA-MB-231, CRL-2335, BR-1126), cisplatin-resistant cell lines, and CSCs with CFM-4.16 and/or cisplatin.
• Analysis of FZD8, LRP6, and c-Myc expression levels.
• Assessment of apoptosis, cell death, and mammosphere formation.
• Evaluation of PARP cleavage.

Main Results:

• CFM-4.16 plus cisplatin significantly enhanced cell death (70-80%) in all TNBC cell lines.
• The combination treatment reduced FZD8 and LRP6 expression and increased apoptosis in cisplatin-resistant cells.
• CFM-4.16 plus cisplatin inhibited CSC mammosphere formation (80-90%) and increased apoptosis in CSCs.
• The combination therapy demonstrated significant apoptosis induction in parental, resistant, and CSC populations.

Conclusions:

• FZD8-mediated Wnt signaling is crucial for CSC growth and chemotherapy resistance in TNBC.
• Inhibiting FZD8-mediated Wnt signaling enhances the chemotherapeutic response in TNBC.
• CFM-4.16 in combination with cisplatin represents a promising therapeutic strategy for overcoming TNBC chemoresistance and preventing tumor recurrence.