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

Triple-negative breast cancer (TNBC) poses a significant challenge due to its high mortality rates, primarily attributed to resistance against chemotherapy regimens containing taxanes like paclitaxel. Thus, developing combinatorial strategies to override resistance is a pressing need. By taking advantage of a library screening with various kinase inhibitors, we found that the small-molecule inhibitor enzastaurin targeting protein kinase C (PKC) could overcome resistance in TNBC cells. Mechanistically, dual treatment with paclitaxel and enzastaurin resulted in efficient mitotic arrest and subsequent cell death by restoring AURKB expression. Further analysis revealed that the GCN2-p-eIF2α axis was responsible for the posttranscriptional accumulation of AURKB upon combinatorial treatment. Finally, we confirmed that combinatorial regimens synergistically suppressed tumour growth in vivo in mouse models. Moreover, the efficiency of dual treatment was largely determined by AURKB, implying that AURKB could be a potential predictive marker for stratifying patients who may benefit from the combinatorial treatment. Collectively, our study not only unravels a novel underlying mechanism for paclitaxel resistance in TNBC but also provides a new potential combinatorial therapeutic strategy in the clinic.