Abstract 5119: Exploring the relationship between metabolism and the epigenome in MYCN-amplified neuroblastoma

Abstract

Abstract Background: Neuroblastoma (NB) is the most common cancer of infancy and is responsible for the most cancer-related deaths in children under the age of five. The transcription factor MYCN is the most studied oncogene in NB and automatically confers high-risk. MYCN drives numerous effects in the cell, including metabolic changes that are critical for oncogenesis. NB has also been demonstrated to be a highly methylated cancer, with DNA methyltransferases (DNMTs) largely responsible for these modifications. Epigenetics and metabolism are closely connected, with oncogene-driven metabolic rewiring modifying the epigenetic landscape through increases of metabolites that are critical for the activities of epigenetic enzymes, and conversely the enhanced epigenetic activity further regulating the activity of metabolic enzymes. Aims: As metabolism is believed to be a key regulator of the epigenome, the objective of this proposal is to understand the connection between MYCN-DNMT1-driven epigenetic alterations and dysregulated metabolism in MYCN-amplified NB. Methods: RNA-seq and mass spectrometry analyses were performed to explore the MYCN-driven metabolome in NB and changes that occur with DNMT1 inhibition. The efficacy of DNMT1 inhibition in MYCN-amplified NB was tested in vivo. Results: Our data demonstrate that sensitivity to DNMT1 inhibition is linked to MYCN status in NB. We found that MYCN indeed dysregulates metabolism in NB, and DNMT1 inhibition led to a global decrease in oxidative phosphorylation and exacerbated mitochondrial dysfunction in MYCN-amplified NB. Expression of MYCN was linked to an increase in methionine and subsequently SAM, the universal methyl donor, further supporting reliance on DNMT1. Most importantly, we have found that treatment with DNMT1 inhibitors in vivo inhibited tumor growth, even after treatment had stopped. Conclusion: We have found a correlation between MYCN and metabolism that supports DNMT1 activity. This relationship allows for a potential treatment for a high-risk disease in which there is few clinically actionable targets. Citation Format: Krista M. Dalton, Timothy L. Lochmann, Colin Coon, Marissa L. Calbert, Mikhail Dozmorov, Lisa Shock, Jennifer Koblinski, Anthony C. Faber. Exploring the relationship between metabolism and the epigenome in MYCN-amplified neuroblastoma [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 5119.