Abstract 5694: Targeting NAD(P)H: Quinone oxidoreductase 1 (NQO1) for colorectal cancer diagnosis and therapy

Background/Objective: Colorectal cancer (CRC) is the third most common cancer in the United States and is associated with poor outcomes. NAD(P)H: Quinone Oxidoreductase 1 (NQO1), an enzyme, shown to contribute to chemoprotection for CRC. This meta-analysis aims to examine the association between NQO1 C609T polymorphisms and CRC risk. Furthermore, the study explores the binding capacity and efficacy of BBI 608 against NQO1 in CRC through molecular docking. The inhibitor will then be tested in vitro. Methods: PubMed, Web of Science, and Google Scholar were used in bibliographic searches. For the NQO1 C609T analysis, 18 studies were used. Data was gathered and subsequently calculated using the pooled odds ratio (OR) (95% confidence interval, CI). Molecular docking, Western Blot, and QRT-PCR were used to determine the molecular function of BBI 608 and NQO1. Results: The relation between NQO1 polymorphism and CRC risk (TT + CT vs. CC: OR=1.19, 95% CI =1.06-1.34, p<0.001) was significant. Furthermore, stratified investigation based on ethnicity indicated a significant association between NQO1 polymorphism and CRC risk (TT + CT vs. CC: OR=1.17, 95% CI =1.08-1.27, p<0.001). This study indicates that the C609T polymorphism of NQO1 is linked with CRC risk in Asians and Caucasians. Computational approaches were applied to observe the molecular properties of BBI 608 (NQO1 inhibitor) and analyze the exact mechanism of NQO1 on CRC. This investigation provides a detailed understanding of the interaction between NQO1 and BBI 608 and its implication in CRC therapy. In vitro studies were performed to support this computational analysis. BBI 608 creates higher cytotoxicity in a dose-dependent manner in CRC cell lines. BBI 608 treatment significantly (p<0.001) reduced the NQO1 expression at protein and RNA levels in both CRC (HCT 116 and RKO) cell lines. Conclusion: Based on meta-analysis and a computational approach, NQO1 is a viable biomarker and a possible molecular target in CRC. In vitro, results showed that inhibiting NQO1 by BBI 608 decreased cell proliferation in both CRC cell lines. Knockout, overexpression, or site-directed mutagenesis is essential for a better understanding of BBI 608-targeted NQO1 and its amino acids. Citation Format: Chaithanya Ganji, Santosh Behera, Lakkakula V. Bhaskar, Mehmet Akce, Bassel F. El-Rayes. Targeting NAD(P)H: Quinone oxidoreductase 1 (NQO1) for colorectal cancer diagnosis and therapy [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 5666.