Abstract 3529: Modulation of MDM2 alters the metabolomic programming of dedifferentiated liposarcoma and its sensitivity to cholesterol inhibition

Abstract

Abstract BACKGROUND: Dedifferentiated liposarcoma (DDLPS) is a highly morbid, mesenchymal tumor characterized by amplification of the 12q chromosomal loci. Although DDLPS are lipid tumors, they produce little lipid. Life expectancy is typically less than 15 months in the advanced setting and standard treatments remain highly toxic. Superior treatment options are clearly needed. Amplification of the MDM2 oncogene that resides in these loci is observed in 100% of all DDLPS; however, to variable levels. Through a negative feedback loop, MDM2 inhibits the tumor suppressive functions of p53 that halts cell growth after cellular stress. Previously, we have reported that MDM2 levels correspond with cellular growth and drug metabolism, but little is known about the effects of MDM2 alterations on global metabolomic profiles. These profiles will help us pinpoint dysregulated pathways that explain, at least partially, the functional effects associated with MDM2 amplification. METHODS: Six DDLPS cell lines were brought directly into culture from patients. MDM2 levels were determined via Western blot and RNA-sequencing. Metabolomics data was generated using the Metabolon platform. Cell viability assays were performed in ZOOM IncuCyte or measured by XTT. Atorvastatin was used to inhibit cholesterol synthesis. MDM2 levels were altered using SAR405838 to raise MDM2 levels and MI-192 to lower MDM2 levels. Synergy was calculated via Chou-Talalay method to determine the combination index (CI) using Compusyn software. RESULTS: MDM2 levels are inversely correlated with metabolites in the lipid and cholesterol pathway (Fisher's, p < 0.001). The lipid metabolism pathway was also the top deregulated pathway (pathway enrichment p-value = 0.03) in transcriptionally profiled DDLPS cell lines treated with MDM2 elevating agent SAR405838. MDM2 low DDLPS cell lines were exquisitely sensitive to HMGA-CoA reductase inhibitors in the low micromolar range. Lipid metabolite profiling of MDM2 low versus high cell lines treated with atorvastatin demonstrated that twice as many lipid metabolites were altered in MDM2 low versus high cells (Chi-square, p < 0.001). MDM2 levels by RNA-seq demonstrated significant correlation between MDM2 gene expression and atorvastatin IC50 doses (r=0.963). MDM2 modulation by use of SAR405838 and MI-192 respectively in combination with atorvastatin displayed antagonism (average CI = 1.5) and synergy (average CI = 0.63), respectively. CONCLUSION: Modulation of MDM2 alters cholesterol metabolism in DDLPS and may serve as druggable target. Citation Format: Bryce Demoret, Andrew Patt, John Hays, Ewy Mathé, James L. Chen. Modulation of MDM2 alters the metabolomic programming of dedifferentiated liposarcoma and its sensitivity to cholesterol inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3529.