In patient-derived IDHWT GBM tumors in vitro and in vivo, cotreatment of BCAT1 inhibitor gabapentin and AKG resulted in synthetic lethality...Partial restoration of ATP, nucleotides, proteins, and mTORC1 activity by BCKA supplementation prevented IDHWT GBM cell death conferred by the combination of BCAT1 loss and AKG. These findings define a targetable metabolic vulnerability in the most common subset of GBM that is currently incurable.

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.

We have previously demonstrated that BCAT1, the enzyme responsible for the reversible transamination of leucine in the cytosol, is a druggable target in immune-oncology: the small molecule inhibitor ERG245 dramatically increases the efficacy of anti-PD-1 treatment in the moderately immunogenic CT26 colon cancer model...Withdrawal of BCAT1 restored or reversed the cell phenotype leading to epigenetically altered CD8+ T cells with decreased histone acetyltransferase and histone demethylase presence, increased cytotoxicity, and increased ribosome biogenesis. Collectively, the data suggest that temporal inhibition of BCAT1 inhibition induces profound effects on CD8+ T cells including increased cytotoxicity and suppression of terminal exhaustion, thus rendering the cells rescuable by anti-PD-1 therapy.

The present results indicated that curcumin may induce apoptosis by inhibiting the BCAT1 and mTOR pathways. Thus, understanding the mechanism underlying curcumin‑induced apoptosis in cytarabine‑resistant cells can support the development of novel drugs for leukemia.

Chromatin immunoprecipitation assays demonstrated that c‑Myc has binding sites in the GLUT1 promoter. Collectively, the present findings suggested that BCAT1 is upregulated in human HNSCC and regulates HNSCC cell proliferation, invasion, cisplatin sensitivity and c‑Myc/GLUT1 signaling.

Our results revealed that FLOT2 promotes NPC cell proliferation by suppressing miR-33b-5p, to maintain proper levels of c-Myc, and upregulate BCAT1trancription. Therefore, the FLOT2/miR-33b-5p/c-Myc/BCAT1 axis is a potential therapeutic target for NPC.

Additionally, BCAT1 correlated with apoptosis, hypoxia and angiogenesis processes in gliomas and high expression of BCAT1 revealed higher glycolysis level and increased immunosuppressive status in tumor progression. We concluded that BCAT1 is a strong prognostic factor for glioma patients and involved in the malignant progression of IDH1 wild-type gliomas.

Withdrawal of ERG245 restored intracellular lactate levels without reversing the metabolic reprogramming of the cells. We propose that these are elements of a mechanism that links temporal inhibition of BCAT1 to the rise of highly energetic CD8+ T cells with increased cytotoxicity and proliferative capacity in vitro and in vivo.