AR/ERK co-targeting triggers ferroptosis via FOXC2 in triple-negative breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options.
• Androgen receptor (AR) is a potential therapeutic target, but AR inhibitor monotherapy shows restricted efficacy.
• Developing novel therapeutic strategies for TNBC is crucial.

Purpose of the Study:

• To identify synergistic drug combinations for TNBC treatment.
• To investigate the therapeutic potential of targeting AR and ERK pathways concurrently.
• To elucidate the underlying mechanisms of combination therapy-induced cell death.

Main Methods:

• Comprehensive drug library screening was performed to identify effective drug combinations.
• Transcriptome sequencing was utilized to analyze the molecular effects of the combination therapy.
• Key molecular mediators, including FOXC2 and the Hippo signaling axis, were investigated.

Main Results:

• The ERK inhibitor GDC-0994 demonstrated significant synergy with the AR inhibitor bicalutamide.
• Combination therapy activated ferroptosis, indicated by increased reactive oxygen species (ROS), elevated Fe2+ levels, and lipid peroxidation.
• FOXC2 was identified as a key mediator, with the combination therapy inhibiting FOXC2-driven epithelial-mesenchymal transition (EMT) and inducing ferroptosis via the FOXC2-Hippo signaling axis.

Conclusions:

• Co-targeting AR and ERK pathways represents a promising therapeutic strategy for TNBC.
• The combination therapy suppresses tumor proliferation, migration, and invasion by inducing ferroptosis and inhibiting EMT.
• This study provides a foundation for developing novel targeted therapies for TNBC.