Metabolic rewiring in MYC-driven medulloblastoma by BET-bromodomain inhibition

Abstract

Medulloblastoma (MB) is the most common malignant brain tumour in children. High-risk MB patients harbouring MYC amplification or overexpression exhibit a very poor prognosis. Aberrant activation of MYC markedly reprograms cell metabolism to sustain tumorigenesis, yet how metabolism is dysregulated in MYC-driven MB is not well understood. Growing evidence unveiled the potential of BET-bromodomain inhibitors (BETis) as next generation agents for treating MYC-driven MB, but whether and how BETis may affect tumour cell metabolism to exert their anticancer activities remains unknown. In this study, we explore the metabolic features characterising MYC-driven MB and examine how these are altered by BET-bromodomain inhibition. To this end, we employed an NMR-based metabolomics approach applied to the MYC-driven MB D283 and D458 cell lines before and after the treatment with the BETi OTX-015. We found that OTX-015 triggers a metabolic shift in both cell lines resulting in increased levels of myo-inositol, glycerophosphocholine, UDP-N-acetylglucosamine, glycine, serine, pantothenate and phosphocholine. Moreover, we show that OTX-015 alters ascorbate and aldarate metabolism, inositol phosphate metabolism, phosphatidylinositol signalling system, glycerophospholipid metabolism, ether lipid metabolism, aminoacyl-tRNA biosynthesis, and glycine, serine and threonine metabolism pathways in both cell lines. These insights provide a metabolic characterisation of MYC-driven childhood MB cell lines, which could pave the way for the discovery of novel druggable pathways. Importantly, these findings will also contribute to understand the downstream effects of BETis on MYC-driven MB, potentially aiding the development of new therapeutic strategies to combat medulloblastoma.

Inhibition of Bromodomain Proteins Enhances Oncolytic HAdVC5 Replication and Efficacy in Pancreatic Ductal Adenocarcinoma (PDAC) Models

“…In support of the cell cycle findings, the cell proliferation marker Ki67 was profoundly reduced over time (24-72 h) in the presence of the inhibitors (Figure 3A). One of the most important proteins that is regulated by the BRD4-associated transcriptional machinery is c-Myc [32,35,36]. The expression of c-Myc in Suit-2 cells was greatly reduced by all three inhibitors when administered alone (Figure 3B; left blot).…”

“…Barasertib, GSK2801, and MLN8054 needed further dose and time optimisation and were not pursued in this study. Both iBET-762 and OTX-015 belong to the bromodomain and extra-terminal motif (BET) protein inhibitors that block binding of bromodomain 4 (BRD4)-containing coactivators to acetylated transcription factors, thereby preventing transcription of target genes [30][31][32]. For example, BRD4-containing proteins play major roles as coactivators of c-Myc expression, which is frequently upregulated in PDAC, and support cancer cell survival and proliferation [33,34].…”

Targeting MYC at the intersection between cancer metabolism and oncoimmunology

“…Another approach is the inhibition of MYC transcription by bromodomain-containing 4 (BRD4), using inhibitors such as JQ1 and OTX-015 ( 162 ). In medulloblastoma, the transcriptional inhibition of MYC by OTX-015 alters cancer glycolysis and amino acid metabolism ( 163 ). Moreover, the use of JQ1 in neuroblastoma, melanoma cells promoted tumor immunogenicity and potentiated immune checkpoint blockade therapy ( 164 ).…”