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Driving with Both Feet: Supplementing AKG While Inhibiting BCAT1 Leads to Synthetic Lethality in GBM
Noah Meurs1,2,3, Deepak Nagrath1,2,3,4,5
1Laboratory for Systems Biology of Human Diseases, Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan.
Abstract:
Understanding how carcinogenesis can expose cancers to synthetically lethal vulnerabilities has been an essential underpinning of development of modern anticancer therapeutics. Isocitrate dehydrogenase wild-type (IDHWT) glioblastoma multiforme (GBM), which is known to have upregulated branched-chain amino acid transaminase 1 (BCAT1) expression, has not had treatments developed to the same extent as the IDH mutant counterpart, despite making up the majority of cases. In this issue, Zhang and colleagues utilize a metabolic screen to identify α-ketoglutarate (AKG) as a synthetically lethal treatment in conjunction with BCAT1 inhibition in IDHWT GBM. These treatments synergize in a multipronged approach that limits substrate catabolism and disrupts mitochondrial homeostasis through perturbing the balance of NAD+/NADH, leading to mTORC1 inhibition and a reduction of nucleotide biosynthesis. Based on these results, the authors propose combination treatment targeting branched chain amino acid catabolism as a potential option for patients with IDHWT GBM. See related article by Zhang et al., p. 2388.
Insights
New research identifies alpha-ketoglutarate (AKG) combined with BCAT1 inhibition as a promising synthetic lethal strategy for treating isocitrate dehydrogenase wild-type glioblastoma multiforme (IDHWT GBM). This combination disrupts cancer cell metabolism and homeostasis, offering a potential new therapeutic avenue.
Area of Science:
- Biochemistry
- Oncology
- Metabolic pathways
Background:
- Isocitrate dehydrogenase wild-type (IDHWT) glioblastoma multiforme (GBM) represents the majority of GBM cases but lacks targeted therapies compared to IDH-mutant GBM.
- IDHWT GBM is characterized by upregulated branched-chain amino acid transaminase 1 (BCAT1) expression, presenting a potential therapeutic target.
Discussion:
- This study identifies alpha-ketoglutarate (AKG) as a synthetically lethal agent when combined with BCAT1 inhibition in IDHWT GBM.
- The synergistic effect disrupts cancer cell metabolism by limiting substrate catabolism and perturbing mitochondrial homeostasis, specifically the NAD+/NADH balance.
Key Insights:
- The combination therapy leads to mTORC1 inhibition and reduced nucleotide biosynthesis, crucial for cancer cell proliferation.
- Targeting branched-chain amino acid catabolism offers a novel therapeutic strategy for IDHWT GBM.
Outlook:
- Further investigation into combination treatments targeting BCAT1 and AKG metabolism is warranted for IDHWT GBM.
- This approach may pave the way for developing effective therapies for a significant patient population currently underserved by treatment options.
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