Targeting PKC as a Therapeutic Strategy to Overcome Chemoresistance in TNBC by Restoring Aurora Kinase B Expression

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Triple-negative breast cancer (TNBC) exhibits high mortality and resistance to standard taxane chemotherapy.
• Overcoming paclitaxel resistance in TNBC is a critical unmet clinical need.

Purpose of the Study:

• To identify novel therapeutic strategies to overcome paclitaxel resistance in TNBC.
• To elucidate the underlying mechanisms of resistance and potential predictive biomarkers.

Main Methods:

• High-throughput screening of kinase inhibitors in combination with paclitaxel.
• Investigated the role of protein kinase C (PKC) inhibitor enzastaurin.
• Analyzed the GCN2-p-eIF2α-AURKB axis in vitro and in vivo tumor models.

Main Results:

• Enzastaurin restored paclitaxel sensitivity in TNBC cells by inducing mitotic arrest and cell death.
• The combination therapy upregulated Aurora Kinase B (AURKB) expression via the GCN2-p-eIF2α pathway.
• Combined paclitaxel and enzastaurin synergistically suppressed tumor growth in preclinical mouse models.
• AURKB expression levels correlated with treatment efficacy, suggesting its potential as a predictive marker.

Conclusions:

• Enzastaurin combined with paclitaxel represents a promising therapeutic strategy for TNBC.
• The GCN2-p-eIF2α-AURKB axis is a key mediator of paclitaxel resistance and a target for overcoming it.
• AURKB may serve as a predictive biomarker for patient stratification in clinical settings.