Driving with Both Feet: Supplementing AKG While Inhibiting BCAT1 Leads to Synthetic Lethality in GBM.
Cancer Res
; 82(13): 2354-2356, 2022 07 05.
Article
em En
| MEDLINE
| ID: mdl-35788291
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.
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Base de dados:
MEDLINE
Assunto principal:
Glioblastoma
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article