Abstract 1052: Augmentation of standard chemotherapy response by inhibition of Aurora kinase A in preclinical models of pancreatic cancer

Abstract

Abstract Background: The prognosis of pancreatic ductal adenocarcinoma (PDAC) is very poor with a 5-year survival rate of 8%. Current standard chemotherapeutic treatment nab-paclitaxel (NPT) plus gemcitabine (Gem) has been able to give an average prognosis of 8.5 months after detection. Aurora Kinase A (AURKA), an enzyme responsible for the regulation of cytokinesis, is mutated in over 55% of PDAC. Increased expression of AURKA inhibits metabolic stress-induced autophagy, thus promoting cell survival. Additionally, amplification of AURKA has been shown to lead to taxane resistance. Through inhibition of AURKA signaling with a small-molecule inhibitor alisertib (MLN8237, ALS), we evaluated an enhancement of NPT+Gem chemotherapy response in PDAC. Methods: In vitro cell proliferation was evaluated in PDAC-associated cell lines by WST-1 assay. Protein expression was measured by Immunoblot analysis. Tumor growth and survival studies were performed using human PDAC cells AsPC-1 in NOD/SCID mice. Intratumoral mechanism of action was determined by IHC and Immunoblot analysis. Results: In AsPC-1 subcutaneous xenografts, chemotherapy regimen (NPT+Gem) and alisertib inhibited tumor growth while their combination exhibited an additive effect. The increase in tumor size was 255 mm3 in controls, 105 mm3 after NPT+Gem, 133 mm3 after ALS and 38 mm3 after NPT+Gem+ALS treatment. In peritoneal dissemination xenografts, animal survival was 23 days in controls that was increased by NPT+Gem (41 days, 78% increase), ALS (25 days, 9% increase) and NPT+Gem+ALS exhibited an additive effect (49 days, 113% increase). NPT+Gem and ALS effect on tumor cell proliferation and apoptosis corresponded with subcutaneous tumor growth data. In vitro proliferation analysis of PDAC epithelial cells (AsPC-1, Panc-1), stromal cells and endothelial cells demonstrated that NPT+Gem and ALS inhibited cell proliferation and their combination treatment had an additive effect. Immunoblot analysis of PDAC cells showed increased levels of cleaved caspase-3 and cleaved PARP-1 in combination therapy pointing to increased levels of apoptosis with NPT+Gem+ALS treatment in all cell lines tested. Conclusion: These findings demonstrate that nab-paclitaxel plus gemcitabine standard chemotherapy response can be enhanced through specific inhibition of aurora kinase A signaling by alisertib in PDAC. The data support the potential of this combinatorial therapeutic strategy for clinical PDAC therapy. Citation Format: David Kronenberger, Margaret A. Schwarz, Md Sazzad Hassan, Urs von Holzen, Roderich E. Schwarz, Niranjan Awasthi. Augmentation of standard chemotherapy response by inhibition of Aurora kinase A in preclinical models of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1052.