Targeting TACC3 Induces Immunogenic Cell Death and Enhances T-DM1 Response in HER2-Positive Breast Cancer

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Trastuzumab emtansine (T-DM1) is a successful antibody-drug conjugate for HER2-positive breast cancer.
• Resistance to T-DM1 is a significant clinical challenge, limiting its long-term efficacy.
• Understanding T-DM1's mechanism of action and resistance is crucial for improving treatment outcomes.

Purpose of the Study:

• To elucidate the mechanism of T-DM1-induced cell death and identify factors contributing to resistance.
• To investigate the role of immunogenic cell death (ICD) in T-DM1 response and resistance.
• To explore TACC3 as a potential therapeutic target for overcoming T-DM1 resistance.

Main Methods:

• In vitro studies using sensitive and resistant cancer cell lines.
• Analysis of ICD markers, including eIF2α phosphorylation, calreticulin exposure, ATP/HMGB1 release, and cytokine secretion.
• Correlation of ICD gene signatures and T-cell infiltration with clinical response data.
• In vivo studies involving TACC3 inhibition in mouse models and vaccination assays.

Main Results:

• T-DM1 induces spindle assembly checkpoint (SAC)-dependent immunogenic cell death (ICD) in sensitive cells, a process lost in resistant cells.
• Overexpression of TACC3 was observed in T-DM1-resistant cells and correlated with poor treatment response.
• Inhibition of TACC3 restored T-DM1-induced SAC activation and ICD markers in vitro.
• TACC3 inhibition potentiated T-DM1 efficacy in vivo by promoting dendritic cell maturation and enhancing anti-tumor T-cell responses.

Conclusions:

• Immunogenic cell death (ICD) is a critical mechanism of action for T-DM1 in HER2-positive breast cancer.
• Loss of ICD induction is a key driver of T-DM1 resistance.
• Targeting TACC3 represents a promising strategy to restore T-DM1-mediated ICD and overcome resistance, improving therapeutic outcomes.