Abstract 6922: MDM2 inhibitor alrizomadlin induces ferroptosis through p53 dependent and independent pathways in TP53 wildtype NSCLC

Abstract Alrizomadlin (APG-115) is a second-generation MDM2 inhibitor that blocks the MDM2-p53 interaction, thereby stabilizing p53 protein and restoring its transcriptional regulatory functions in cell cycle control and apoptosis. Recent study indicated that APG-115 also exerted an anticancer effect in various cancers, but the specific function and underlying mechanism in TP53-wildtype NSCLC has not been elucidated. My project aims to determine whether APG-115 exerts anti-tumor effects by mediating ferroptosis through P53 dependent and non dependent pathways. We repeatedly validated the induction effect of APG-115 on ferroptosis using multiple recognized iron death detection methods, searched for ubiquitinases in public databases, and constructed a mouse tumor model to further verify the in vitro experimental results. In this study, we found that APG-115 exerted potent antitumor efficacy in TP53-wildtype NSCLC both in vitro and in vivo. Further experiments demonstrated that APG-115 induced ferroptosis, thereby facilitating the tumor cell death. Ferroptosis -related pathways genes, such as PTGS2, were significantly enriched after APG-115 treatment. APG-115 promotes PTGS2-mediated ferroptosis through a well-characterized mechanism. Specifically, APG-115 upregulates the expression of the deubiquitinase USP22, a key regulator in protein homeostasis. USP22, once upregulated, acts on PTGS2 by removing its ubiquitin tags through the ubiquitin-proteasome system. This deubiquitination prevents PTGS2 from being targeted for proteasomal degradation, thereby stabilizing the PTGS2 protein. The sustained expression of PTGS2 enhances ferroptosis, ultimately contributing to the cytotoxic effects of APG-115 in tumor cells. Collectively, our study reveals that APG-115 induces ferroptosis in TP53-wildtype NSCLC by stabilizing the expression of PTGS2 protein, providing a new direction for further clinical investigation of APG-115 as a monotherapy or combination therapy.Keywords:Alrizomadlin; Ferroptosis; PTGS2; USP22; Ubiquitin-proteasome system Citation Format: Shan Shi, Qiu Yun Luo, Wen Tao Pan, Miaozhen Qiu, Da Jun Yang. MDM2 inhibitor alrizomadlin induces ferroptosis through p53 dependent and independent pathways in TP53 wildtype NSCLC [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 6922.