Abstract LB061: Aurora kinases inhibition enhances neoadjuvant chemotherapy response in triple negative breast cancer

Abstract Triple-Negative Breast Cancer (TNBC) is a type of breast cancer without expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2). TNBC accounts for around 15-20% of all breast cancers, and it remains the most challenging subtype to treat because of its aggressive phenotype and limited treatment strategies. Since TNBC does not respond to endocrine and HER2-targeted therapy, chemotherapy and anti-PD-L1 immunotherapy remain the major treatment strategies so far. However, not all TNBC patients respond to chemotherapy, suggesting that TNBC is a complicated disease. Identifying biomarkers to further predict and subdivide TNBC patients with distinct chemotherapy responses and outcomes is very important. To profile the protein expression and phosphorylation alterations, comprehensive proteogenomics was deployed to probe the molecular basis for differential response to neoadjuvant chemotherapy for TNBC. From a Reverse Phase Protein Array (RPPA) on TNBC cell lines MDA-MB-468 cells and MDA-MB-231 cells treated with Docetaxel, Paclitaxel, Epirubicin, and Doxorubicin, we found only a short list of protein changes after chemotherapy. Among them, the most significant changes in protein are phosphor-AURKA/B/C, AURKA, AURKB, and PLK1, which fall into the mitotic kinase group and are confirmed by western blot analysis. In addition, no significant change in the mRNA level was found after chemotherapy treatment, suggesting a post-transcription level molecular mechanism regulates the upregulation of AURKA and AURKB protein. In fact, the protein level of AURKB decreased more significantly with Cycloheximide (CHX) treatment alone compared with the co-treatment of CHX and Paclitaxel, indicating Paclitaxel extended the lifetime of Aurora Kinases protein and increased the protein stability. Moreover, AURKB or AURKA overexpression in TNBC cells renders them resistant to Paclitaxel treatment and attenuates the apoptosis effect triggered by chemotherapy treatment, suggesting Aurora Kinases could mediate the chemo-resistance in TNBC. To overcome the resistance to chemotherapy, we treated resistant TNBC cells with the combination of Aurora kinase inhibitors and anthracycline/taxane chemotherapy and found that Aurora kinase inhibition significantly enhanced the chemotherapy effect. In summary, we found that Aurora Kinases upregulation by treatment with Taxanes-type and Anthracyclines-type chemotherapy could render chemotherapy resistance to TNBC cells. Citation Format: Jia Xu, Chang Liu, Bohan Ning, Ali Cem Kucukdagli, Yunjia Chen. Aurora kinases inhibition enhances neoadjuvant chemotherapy response in triple negative breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB061.