Abstract 4593: A synergy between MDM2 and AURKB pathways in driving cell cycle and cell survival in lung cancer cells

Abstract

Abstract Lung cancer is the leading cause of cancer-related deaths worldwide and non-small cell lung cancer (NSCLC) is the most prevalent type among lung cancers, contributing to the high mortality seen with this deadly disease. Despite aggressive treatments, the 5-year survival rate for lung cancer is only 23.7% in the United States. MDM2 and AURKB are two cancer-driving genes that are highly expressed in a broad range of cancer types including lung cancers. Furthermore, MDM2 overexpression can positively impact AURKB expression and contribute to oncogenesis and cancer progression. Therefore, blocking MDM2 with specific inhibitors has become a promising strategy for the restoration of p53 function that could be used for the treatment of different types of cancers including lung cancers. In this regard, both MDM2 and AURKB inhibitors have shown promising antitumor activity against NSCLC. Therefore, the main objective of this study was to understand the molecular mechanisms linking MDM2 and ARKB using RG7388, CM272, BMS-582949 (p38 inhibitor), and Ralimetinib (p38 inhibitor) in A549 and H460 lung cancer cells. We analyzed the individual or combination treatment effects of these drugs on epigenetic modifications, cell cycle arrest, and cell death mechanisms, using the in vitro experimental model. When RG7388 was used individually, or in combination with BMS-582949 or Ralimetinib, a significant increase in the cytotoxic effect was observed in A549 and H460 cells. Induction of cell cycle arrest by RG7388 in cancer cells was evidenced by elevated p21 expression levels. In addition, RG7388 and combination treatments in NSCLC cells showed significant upregulation of p53, p27, Bax, cleaved PARP, phospho-FOXO3a and down-regulation in DNMT3a, DNMT1, FOXM1, AURKB, CDC25, and CDK4 levels. It appears that during treatments with a combination of MDM2 with DNMT or p38 inhibitor, two pathways might be blocked simultaneously, which could lead to increased cancer cell death. RG7388 appears to induce cell death in a p21-dependent manner and CM272, BMS-582949, and Ralimetinib seem to induce cell death via a p21-independent manner by inhibiting a downstream pathway. However, further studies are needed to fully understand the intracellular link between MDM2 and AURKB that is disrupted by the anti-cancer agents used in our study. (This project was supported by the PFRDG Grant of Nova Southeastern University and by the Generous support from the Royal Dames of Cancer Research Ft. Lauderdale, FL) Citation Format: Umamaheswari Natarajan, Appu Rathinavelu. A synergy between MDM2 and AURKB pathways in driving cell cycle and cell survival in lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4593.