Abstract 3929: MDMX overexpression in cancer cells confers significant resistance to MDMX inhibitor XI-006 and may modulate chemosensitivity through suppressing p53 activation of pro-apoptotic factors

Abstract

Abstract MDM2 inhibition has gained popularity in recent years as a therapeutic strategy in targeting both solid tumors and hematological malignancies, and several small molecule inhibitors of the p53-MDM2 binding interface have progressed into clinical trials in recent years. Alongside direct stabilization of p53, MDM2 has further been identified to have immune implications in terms of CD8+ T-cell mediated anti-tumor immunity and checkpoint-blockade therapies. However, little work has been done to explore the therapeutic targeting potential of related protein MDMX (MDM4). Pan-cancer analyses conducted by our lab (in part presented at the ASCO 2022 Annual Meeting) identify an important role of MDMX in several tumor types. Particularly, MDMX amplification is associated with a higher risk of brain and liver metastasis, and MDMX amplification itself also presents with significant frequency (10%) in glioblastoma multiforme (GBM). Notably, MDMX amplification also served as a better predictor of reduced overall survival in NSCLC following checkpoint-blockade. We have also previously reported on associations between MDMX amplification and CDKN2A deep deletions in melanoma, a predictor of favorable response to checkpoint blockade. Such findings establish the need for further exploration to be done and the role of MDMX both in cell phenotype and potential immune regulation to be better characterized. Preliminary data acquired from transient overexpression experiments using lipofection of MDMX cDNA and MDMX inhibitor XI-006 (NSC207895) alone and in combination with chemotherapy further supports the viability of MDMX-inhibition as a therapeutic strategy in several cell lines. Overexpression of MDMX in HCT116 p53WT cells demonstrably confers remarkable resistance to MDMX inhibitor XI-006 at a 72-hour timepoint (IC50 of 104.75 uM in overexpressing cells versus 29.03 uM in WT), and treatment with oxaliplatin reveals both reduced basal and post-treatment expression of p53-upregulated modulator of apoptosis (PUMA). Further mechanistic workup of this phenomenon is underway, particularly with an emphasis on immuno-oncological therapeutic translations. Altogether, initial findings ultimately establish the need for further investigation into the mechanistic basis of MDMX-correlated clinical outcomes and the therapeutic potential of MDMX inhibition. Citation Format: Andrew George, Arielle De La Cruz, Shengliang Zhang, Ilyas Sahin, Praveen Srinivasan, Maximilian Schwermann, Morgan Turcotte, Taylor Arnoff, Wafik S. El-Deiry. MDMX overexpression in cancer cells confers significant resistance to MDMX inhibitor XI-006 and may modulate chemosensitivity through suppressing p53 activation of pro-apoptotic factors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3929.