Abstract 441: Evaluation of the effects of MDM2 inhibitor and epigenetic modifiers in combination with AURKB inhibitors for treating lung cancer

Abstract Lung cancer remains one of the leading causes of cancer-related deaths globally, primarily due to its aggressive nature, high metastatic potential and resistance to treatment. It is classified into two main subtypes: non-small cell lung cancer (NSCLC), which accounts for approximately 85% of cases, and small cell lung cancer (SCLC), making up the remaining 15%. Despite significant advances in early detection and treatment, lung cancer continues to pose a major challenge because of its resistance to therapy and its ability to metastasize rapidly. A promising avenue for more effective treatments lies in understanding the molecular mechanisms that can trigger lung cancer progression. Specifically, Aurora kinase B (AURKB) has emerged as an important oncogenic protein involved in regulating cell cycle progression, and its dysregulation is implicated in various cancers, including lung cancer. The interaction of AURKB with MDM2 is of interest due to its potential role in tumor progression and resistance to chemotherapy. In this study, we aimed to explore the relationship between AURKB and MDM2 in lung cancer cells, to determine where and how these proteins interact to support cancer growth. We also examined the anti-cancer effects of RG-7388, SAHA, CM-272, and Barasertib (an AURKB inhibitor), in modulating cell cycle regulation. Our results demonstrate that inhibition of AURKB induces cell cycle arrest and apoptosis in lung cancer cells. Additionally, treatment with RG-7388 activates the p53 pathway, leading to upregulation of p21 and subsequent cell cycle arrest and cell death. Interestingly, SAHA and CM272 both exhibited inhibitory effects on tumor growth by modulating AURKB through other regulatory proteins. Western blot and Immunofluorescence analysis of A549 and H460 cells after drug treatments, revealed differential responses of protein involved in cell cycle regulation, Cell Death, and epigenetic alterations. Interestingly, treatment of A549 and H460 cells with RG-7388, CM-272, and SAHA) led to upregulation of p53, p21, p27, ALDH1A1, PARP, BAX, Caspases 3, and Caspases 7. On the other hand, MDM2, AURKB, CDC25C, Cyclin A, Cyclin D, CDK4, CDK6, BCl-XL, and XIAP levels were downregulated after above mentioned treatments. Our findings confirm that AURKB levels can be down-regulated by using the combination of MDM2 inhibitors and epigenetic regulators such as SAHA and CM-272. However, the therapeutic efficiency of these combinations needs to be verified using in vivo experimental models. Funding & Acknowledgements: This work was supported by the President's Faculty Research and Development Grant and also the authors would like to thank Royal Dames of Cancer Research, Inc. (Ft. Lauderdale, FL, USA) for their financial support in conducting this research. Citation Format: Neha Tumati, Umamaheswari Natarajan, Shyam Sundar Jaganathan, Appu Rathinavelu. Evaluation of the effects of MDM2 inhibitor and epigenetic modifiers in combination with AURKB inhibitors for treating lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 441.