Targeting Glutaminolysis Shows Efficacy in Both Prednisolone-Sensitive and in Metabolically Rewired Prednisolone-Resistant B-Cell Chi

by Selleckchem | Aug 29 2023

The prognosis for patients with relapsed childhood acute lymphoblastic leukaemia (cALL) remains poor. The main reason for treatment failure is drug resistance, most commonly to glucocorticoids (GCs). The molecular differences between prednisolone-sensitive and -resistant lymphoblasts are not well-studied, thereby precluding the development of novel and targeted therapies. Therefore, the aim of this work was to elucidate at least some aspects of the molecular differences between matched pairs of GC-sensitive and -resistant cell lines. To address this, we carried out an integrated transcriptomic and metabolomic analysis, which revealed that lack of response to prednisolone may be underpinned by alterations in oxidative phosphorylation, glycolysis, amino acid, pyruvate and nucleotide biosynthesis, as well as activation of mTORC1 and MYC signalling, which are also known to control cell metabolism. In an attempt to explore the potential therapeutic effect of inhibiting one of the hits from our analysis, we targeted the glutamine-glutamate-α-ketoglutarate axis by three different strategies, all of which impaired mitochondrial respiration and ATP production and induced apoptosis. Thereby, we report that prednisolone resistance may be accompanied by considerable rewiring of transcriptional and biosynthesis programs. Among other druggable targets that were identified in this study, inhibition of glutamine metabolism presents a potential therapeutic approach in GC-sensitive, but more importantly, in GC-resistant cALL cells. Lastly, these findings may be clinically relevant in the context of relapse-in publicly available datasets, we found gene expression patterns suggesting that in vivo drug resistance is characterised by similar metabolic dysregulation to what we found in our in vitro model.

Comments:

The passage you provided describes a study aimed at understanding the molecular differences between glucocorticoid (GC)-sensitive and -resistant cells in childhood acute lymphoblastic leukemia (cALL). Relapsed cALL often has a poor prognosis due to drug resistance, particularly to glucocorticoids. The researchers conducted an integrated analysis of gene expression (transcriptomic) and metabolite profiles (metabolomic) to uncover potential mechanisms underlying prednisolone resistance.

The study revealed several molecular alterations associated with lack of response to prednisolone. These alterations involve changes in oxidative phosphorylation (a cellular process that generates energy), glycolysis (a metabolic pathway for glucose breakdown), amino acid metabolism, pyruvate and nucleotide biosynthesis, as well as activation of mammalian target of rapamycin complex 1 (mTORC1) and MYC signaling pathways. These pathways are known to play important roles in controlling cell metabolism.

To explore potential therapeutic strategies, the researchers focused on targeting the glutamine-glutamate-α-ketoglutarate axis through three different approaches. Inhibiting this axis impaired mitochondrial respiration (the process of generating energy in mitochondria) and ATP production (the energy currency of cells), ultimately inducing apoptosis (cell death). This suggests that inhibiting glutamine metabolism could be a potential therapeutic approach for both GC-sensitive and GC-resistant cALL cells.

Furthermore, the study found that the gene expression patterns observed in their in vitro model were consistent with those observed in publicly available datasets of relapsed cALL patients. This suggests that the metabolic dysregulation identified in the study may have clinical relevance in the context of cALL relapse.

Overall, the findings of this study shed light on the molecular differences between GC-sensitive and GC-resistant cALL cells. The identification of potential therapeutic targets, such as glutamine metabolism, provides insights for the development of novel and targeted therapies to overcome drug resistance in childhood acute lymphoblastic leukemia.